Chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression

Good news! Cancer is history (soon)!

"Type II interferon (IFN-II) normally activates the immune system to fight cancer. However, prolonged IFN-II exposure can promote an immunosuppressive tumor environment that supports cancer growth, a confounding factor in cancer therapies. Johnson et al. explored why IFN-driven inflammation can be tumor suppressive in certain contexts but tumor promoting in others.

Chronic IFN-II stimulation unveiled secondary protumorigenic type I IFN (IFN-I) signaling that increased production of prostaglandins, bioactive lipids that inhibit anticancer immune responses.

Suppressing prostaglandin synthesis restored the ability of the immune system to attack tumors and reversed resistance to immunotherapy in melanoma cells.

The IFN-II–mediated IFN-I response was instigated by the release of mitochondrial RNA that activated innate immune signaling.

Timely inhibition of IFN-I signaling or blocking mitochondrial RNA release may therefore provide a means to promote antitumor immunity."

"Highlights

• ... researchers identify what flips a molecular “switch” that causes anti-cancer interferon activity to transition into pro-cancer activity, a longstanding mystery in cancer biology
• Chronic interferon activates a mitochondrial signaling pathway that, when turned off, effectively reverses tumor growth and immunotherapy resistance in a mouse model of melanoma
• The study could reveal new therapeutic targets to sustain anti-tumor immune responses

..."

From the abstract:

"Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells.

Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system.

In this study, we sought to determine the cellular mechanisms underlying this switch from antitumorigenic to protumorigenic interferon activity.

We show that chronic type II interferon (IFN-II) exposure distinctively induced tumor growth by activating a type I interferon (IFN-I) response mediated by release of double-stranded mitochondrial RNA (ds-mtRNA) into the cytoplasm. This IFN-I signal synergized with IFN-II to enhance tumor growth by increasing immunosuppressive prostaglandin E2 (PGE2) synthesis through increased cyclooxygenase 2 expression.

Elimination of PGE2 synthesis in immunotherapy-resistant melanoma cells restored their responsiveness to anti-PD1 treatment, indicating that this covert mtRNA-IFN-prostaglandin pathway could be a therapeutic target to combat immunotherapy resistance."

In Science Journals | Science

Why does the immune system sometimes help tumors grow? (original news release) "Salk Institute researchers define how chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression in mice, revealing a key target to sustain anti-tumor immune responses and combat immunotherapy-resistant cancer"

Chronic type II interferon promotes tumor growth through mitochondrial RNA–induced type I interferon and prostaglandin synthesis (no public access)

Representative images showing mitochondrial RNA (mtRNA) transcripts (red) present outside of the confines of mitochondria (cyan) in a melanoma cell following chronic interferon II exposure. Arrows point to specific examples of mtRNA outside the mitochondria.

New clues suggest how destructive immune cells wreak havoc in the brain from the neck

Good news! The best part is that a treatment of the lymph nodes in the neck can be very effective.

"In recent years, scientists have found CD8+ T cells—immune cells that recognize and respond to foreign threats—in the brain tissue of people who died with Alzheimer’s, and evidence suggests that they were harming, not helping. Now, researchers report that a type of dendritic cell in lymph nodes in the neck helps prime these T cells to multiply before they enter the brain and cause damage.

In mice bred to produce excess toxic tau, a key Alzheimer’s protein, those with the dendritic cells developed the expected severe brain damage.

Animals without the dendritic cells did not experience the same T cell infiltration, severe neurodegeneration or behavioral problems—even though they still had excess tau.

This finding suggests that while tau may not be completely harmless by itself, inflammation driven by T cells may amplify the damage. The T cells proliferated in the mice’s neck lymph nodes, where they were primed by the dendritic cells. The fact that this process occurs in the neck, not the brain, opens the door to using existing drugs that trap T cells in lymph nodes. ..."

"... Researchers ... have now discovered in mice that these immune cells, known as T cells, are receiving their instructions from lymph nodes outside of the brain. The team also showed they can block these instructions to dramatically mitigate neurodegeneration. The discovery reveals a previously unsuspected pathway that could potentially halt or slow the progression of Alzheimer’s disease and other diseases collectively called primary tauopathies ..."

From the abstract:

"Alzheimer’s disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity.

However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear.

In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells.

We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation.

The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming.

We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation.

Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration."

ScienceAdviser

New clues suggest how destructive immune cells wreak havoc in the brain (no public access) "Study in mice strengthens T cells’ ties to neurodegenerative conditions like Alzheimer’s"

Key path to Alzheimer’s-like brain damage starts outside the brain (original news release) "Study finds in mice that immune cells that drive neurodegeneration originate in body’s lymph nodes"

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration (open access)

Fig. 4: cDC1 deficiency specifically prevents CD8+ T cells from accumulating in brain of tauopathy mice at 9.5 months of age.

Cancer cells release antioxidants to prevent immune cells from destroying them

Good news! Cancer is history (soon)! Are we finally cracking the secretes how cancer survives/counteracts immune responses and immunotherapy? 

"Now, scientists have discovered that certain immune cells depend on these very molecules to activate and destroy cancer cells, and that tumours exploit this dependency by releasing natural antioxidants to shut down the immune attack. ...

A team ... analysed the fluid surrounding cells within tumours grown in mice and found that cancers chemically ‘smother’ T cells, stopping their activation and preventing them from destroying cancer cells.

Tumours do this by releasing large amounts of a protein that is a natural antioxidant, Peroxiredoxin 1 (PRDX1), which mops up reactive oxygen species and deprives T cells of the activating signals they need to perform cancer killing.

Next, the team used CRISPR gene-editing technology to create mouse cancer cells that could no longer make the antioxidant protein. They found that removing the capacity for the cancer cells to produce the antioxidant promoted immune-cell activity and limited tumour growth. 

Finally, the team looked for the same mechanism in people. They analysed published data on the proteins released by human cancer cell lines, examined gene activity across thousands of human tumours, and isolated the fluid surrounding tumours removed from patients. All three approaches pointed the same way: human cancers also release PRDX1 into their surroundings, where it can strip away the reactive oxygen species that T cells depend on. ...

The findings also carry broader implications. Several large randomised clinical trials have found that antioxidant supplements fail to reduce cancer risk ..."

"New research reveals a promising new target for treating cancer by harnessing a type of molecule previously thought to do more harm than good.

For decades, reactive oxygen species, or ROS, often called free radicals, have been viewed primarily as harmful molecules linked to aging, DNA damage and cancer. A new study ... finds that cancer-fighting T cells need small amounts of ROS to attack tumors.

The investigators discovered that cancers exploit the T cell need for ROS by releasing an antioxidant protein that removes ROS from the tumor environment, effectively shutting down the attack by the immune system upon the cancer. ..."

From the editor's summary and abstract:

"Editor’s summary

Reactive oxygen species (ROS) have a paradoxical role in cancer.

Low to moderate ROS levels can stimulate tumor growth, whereas excessive ROS accumulation triggers oxidative stress and DNA damage.

Antioxidant therapies aim to neutralize free radicals and reduce oxidative stress, but clinical trials have not (yet) demonstrated improved cancer survival. Wesolowski et al. report that tumors can turn ROS dependency against the immune system, suppressing T cells and escaping antitumor immunity. 

Cancer cells secrete antioxidant enzymes, including peroxiredoxin 1 (PRDX1), into the extracellular space, depriving T cells of ROS needed for T cells to attack tumors effectively.

Removing PRDX1 from cancer cells restored antitumor immunity and made otherwise resistant tumors sensitive to checkpoint blockade immunotherapy.

These results suggest that targeting extracellular redox mechanisms could enhance the efficacy of immunotherapy.

Abstract

Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes.

Emerging data suggest that T cells depend on ROS for signal transduction. 

In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell–mediated antitumor immunity.

The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor–driven kinase signaling and effector function.

Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses.

These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention."

Cancer cells release antioxidants to prevent immune cells from destroying them | University of Cambridge (original news release 1) "Molecules called reactive oxygen species, which include so-called 'free radicals', have long been viewed as damaging byproducts of our body’s metabolism – a reason why antioxidant supplements have been considered as a potential way of reducing cancer risk."

Cancer cells use antioxidant protein to suppress T cells, resist immunotherapy, study finds (original news release 2) "OHSU co-author helps identify potential therapeutic target in tumors that evade the immune system"

Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species (no public access)

Killer T cells surrounding a cancer cell

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Good news, but a very small sample size! Impressive!

"Immunotherapies such as CAR T-cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases.

Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In the journal Nature Medicine*, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis. ...

Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication ...

For the world’s first clinical trial to evaluate the safety and efficacy of a CD19 CAR T-cell therapy in rheumatoid arthritis, the research team ... initially enrolled six patients with particularly severe disease. The three women and three men, aged 31 to 69, had received up to eight targeted or biologic therapies over the previous ten years, none of which had been sufficiently effective. ...

For the researchers, the results from the first part of the COMPARE trial are highly encouraging: “Disease activity decreased markedly in all six patients. During follow-up of up to one year, three patients were in sustained remission without any medication for rheumatoid arthritis,” ..."

From the abstract:

"Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases.

Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA).

Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy.

Patients were followed for 36–52 weeks for safety and efficacy.

Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment.

Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses.

CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae).

The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2.

CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M.

Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients).

CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ..."

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Charité study demonstrates efficacy of CD19 CAR T cells in first patients  (original news release)

CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial (no public access)

Patients own immune cells genetically modified in the laboratory, track down the disease driving B cells, even deep within tissues. Inflammatory foci such as those seen here around the knee joints of a study participant (magenta) are no longer detectable even several months after CD19-CAR T-cell therapy (right in the PET-MRI image). Swelling and pain have subsided, with improved mobility.

Cancer-killing cells in those humans live to 110 or longer

Amazing stuff! Good news! Cancer is history (soon)!

"People who live to 110 years and older have large populations of a rare type of immune cell that can kill cancer.

These killer T cells might help people to live to extraordinarily long ages by fighting off cancer — although this has yet to be proved.

“Most of immune ageing research has focused on decline,” [what a mistake!] ... “Our study suggests that even at extreme old age, the immune system may still selectively adapt.”"

"The current study builds on a 2019 finding by Hashimoto and his colleagues that supercentenarians have relatively large numbers of rare CD4 cytotoxic T lymphocytes (CD4 CTLs).

Cytotoxic cells kill other cells. CD4 CTLs typically make up less than 5% of the total population of T cells in the body. They’re not as well studied as other kinds of T cell, but they are commonly detected during viral infections, and there’s increasing evidence that they can kill cancer cells, including lung cancer and melanoma cells. Hashimoto says that his team wanted to find out at what age CD4 CTLs proliferate.

Supercentenarians are challenging to study because not many people live that long, says Hashimoto. In Japan, where his team did the study, there are only about 150 people aged 110 or older, he says. The study enrolled 28 participants, including some relatively young people: eight individuals aged 70–90, ten centenarians (people 100–109 years old) and ten supercentenarians.

As the researchers had previously found, CD4 CTLs were abundant in supercentenarians. But they were also found in large numbers in people aged 100 and older, suggesting that this immune adaptation begins around that age. The younger people had normal abundance of these cells, with CD4 CTLs making up 4% of their total T cells. The proportion was around 10% in centenarians and around 18% in supercentenarians.

And they found that these cells seem to be responding to specific immune threats. ... In the study’s centenarians and supercentenarians, the researchers found that single clonal lines made up a large percentage of the total CD4 CTLs. In the sample of one centenarian, for example, 53.8% of the cells were identical to each other. This suggests that their immune systems were leaping into action in response to a particular persistent trigger. ...

To get some clues, they examined the receptors found on the most common CD4 killer cell lines. They compared the amino-acid sequences of these cell lines with those in a database of CD4 cell receptors. Around 30 sequences from the study matched those from people with cancer in the database. Matches to people with lung cancer were most frequent, even though none of the people in the study had experienced any kind of cancer during their lives. ..."

From the highlights and abstract:

"Highlights

• CD4 CTLs expand around age 100 without signs of exhaustion

• A CD27−CD28+ state marks the intermediate helper-to-killer transition

• Large private CD4 CTL clones suggest repeated antigen exposure

• Single clones diversify cytokine profiles after ex vivo stimulation

Summary

Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians.

CD4 CTLs have primarily been studied in disease contexts; however, their role in healthy aging remains unclear.

Using single-cell immune profiling, we analyzed T cells from supercentenarians and found that CD4 CTLs begin to expand around the age of 100, characterized by sequential CD27/CD28 loss without exhaustion.

CD4 CTLs were dominated by large clones, with top clones averaging 33.3%, indicating repeated stimulation by persistent antigens.

Furthermore, CDR3β sequences of the top clones matched those of T cells expanded in tumors, particularly lung cancer.

Ex vivo stimulation experiments revealed that CD4 CTLs consist of subgroups defined by interleukin expression patterns, suggesting their plasticity within the same clone.

These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression."

Nature Briefing: Cancer

How do people live beyond 110? Abundance of cancer-killing cells might be key "Research on people 110 years and older reveals an immune system that continues to adapt."

CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging (open access)

Misao Okawa celebrated her 117th birthday in 2015. Is she still alive?

Graphical abstract

Figure 1 Overview of single-cell immune profiling

Figure 6 Characteristics of activated CD4 CTLs

Why immune responses to vaccines vary from person to person and how to predict a vaccine response before vaccination

Good news! A still open question how much of the humoral immune response is inherited and how much is due to lifetime training of the immune system of an individual.

"... In blood samples from more than 4,000 people, ASU researchers and their colleagues measured antibodies against 185 antigens—targets recognized by the immune system, including those from common viruses and bacteria as well as targets associated with autoimmune diseases.

They then used artificial intelligence to analyze patterns in samples collected before and after COVID-19 vaccination, identifying antibody signatures that helped distinguish strong vaccine responders from weak ones.

The research opens a possible path toward more personalized vaccination strategies.

"What our study found is that certain biomarkers, when analyzed with AI, can predict who is likely to respond well to a vaccine, even before they receive it. This suggests that some people may be more immune-ready than others," ..."

From the highlights and abstract:

"Highlights

• Pre-existing antibodies to common microbes predict new vaccine response robustness

• These sentinel antibodies are stable markers of humoral immune readiness

• AI models use global antibody profiles to stratify high and low vaccine responders

• Blunted vaccine responses occur in both immunosuppressed and healthy individuals

Summary

Predicting which individuals will mount poor antibody responses before vaccination could improve personalized vaccination strategies.

Here, we conducted a national longitudinal study of humoral immune responses to 185 antigens, including SARS-CoV-2 (n = 3), common microbial pathogens (n = 157), and autoantigens (n = 25), in 1,644 immunosuppressed patients and 2,445 healthy individuals before and after COVID-19 vaccination.

Although blunted COVID-19 vaccine responses were more frequent in solid organ transplant recipients and individuals with multiple myeloma, autoimmune disease, inflammatory bowel disease, and human immunodeficiency virus, responses were highly heterogeneous within every cohort, and approximately 5%–6% of healthy individuals also mounted weak responses.

Pre-existing antibodies to common microbes, including Staphylococcus aureus, respiratory syncytial virus, and human respirovirus 3, consistently predicted post-vaccination antibody responses in both healthy and immunosuppressed populations.

These broadly prevalent antimicrobial antibodies represent sentinel antibodies that may serve as biomarkers of system-level humoral immune competence.

Using global antimicrobial antibody profiles, we developed a deep-learning predictive model that stratified individuals according to their likelihood of mounting blunted vaccine responses.

Together, these findings identify pre-existing antimicrobial antibody profiles as scalable biomarkers of humoral immune responsiveness and provide a framework for predicting vaccine responses before immunization."

Why immune responses to vaccines vary from person to person

Why immune responses to vaccines vary from person to person (original news release) "Study finds past immune encounters may predict future vaccine response"

Pre-vaccine sentinel antibodies predict blunted vaccine responses (open access)

Graphical abstract

Figure 2 The multiplexed humoral immune profiling of 8,687 individual samples among seven cohorts

Figure 7 Pre-existing antimicrobial antibody profiles predict healthy individuals with low vaccine response to COVID-19 booster

Scientists harness nature to engineer stronger CAR-T cells by switching CAR signalling and receptor shedding

Good news! Cancer is history (soon)!

"In brief

• Stanford Medicine researchers developed a CAR-T cell design, called the AIR platform, that uses a natural protein-shedding process to reduce unwanted signaling.
• In cell and mouse studies, AIR-equipped CAR-T cells showed less exhaustion and stronger antitumor activity.
• By mimicking natural immune regulation, the approach could help advance future CAR-T treatment options for patients with solid tumors.

...

While impressively fatal against blood and lymphatic cancers, CAR-T cells hit barricades in the harsher solid-tumor environment, inhibiting their success. A chief obstacle is tonic signaling, which occurs when the CAR is continuously alert and the cell is trigger-ready, even if its antigen is nowhere nearby. ... CAR-T cells become exhausted and dysfunctional, dehydrating their ability to track and kill their targets. ..."

From the highlights and abstract:

"Highlights

• A 15-aa AIR motif endows activation-induced receptor shedding in human T cells

• AIR tunes tonic signaling CARs, reducing exhaustion and improving anti-tumor potency

• AIR improves CAR activity by selectively dampening NFAT signaling and limiting AICD

• AIR enables logic-gated CARs and activation-shed FAS/TGFBR2 to enhance tumor control

Summary

We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation.

Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation—termed activation-induced release (AIR).

Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency.

In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation.

AIR’s modularity supports higher-order logic-gating;

AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR.

Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions.

AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies."

Scientists harness nature to engineer stronger CAR-T cells | Stanford Report "Taking inspiration from biology, Stanford researchers developed a CAR-T cell design that improved tumor control in mice."

Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis

Graphical abstract

Figure 1. Characterization of the T cell surfaceome identifies proteins with activation-dependent surface expression, and analysis of the minimal regions required for surface downregulation

Scientists capture macrophages immune cells attacking live melanoma

Good news! Cancer is history (soon)!

"... a previously overlooked population of immune cells called macrophages that patrol the edges of melanoma tumours, steadily engulfing cancer cells and slowing tumour growth. ...

“This is the first time anyone has captured a macrophage attacking and engulfing a live cancer cell in real time,” ..."

From the abstract:

"Macrophages in the skin reside in multiple distinct layers and perform various functions. Here, we show that CD169+ macrophages reside in the hypodermis and comprise the major skin myeloid cell population in the steady state.

In a syngeneic melanoma model, CD169+ macrophages encapsulate growing melanomas and directly suppress their growth.

CSF1R blockade depleted CD169+ macrophages in tumors and resulted in unrestrained growth.

This local containment of tumor growth in the skin was independent of CD169+ subcapsular sinus macrophages in the tumor-draining lymph node and did not require B or T cells.

Intravital imaging revealed engulfment and ingestion of live tumor cells by CD169+ macrophages.

This phagocytosis did not require the phosphatidylserine receptor MERTK. CD169+ macrophages are also enriched in the hypodermis in skin biopsies from healthy human skin and melanoma.

These data identify tissue-resident CD169+ macrophages as a potential cellular target to achieve innate immune containment and reinforce adaptive immune control of tumors."

Garvan scientists capture ‘housekeeping’ immune cells attacking live melanoma | Garvan Institute of Medical Research "Macrophage immune cells were imaged engulfing live cancer cells – opening a new approach for melanoma treatment."

CSF1R-dependent CD169-positive macrophages locally constrain melanoma growth in the skin

A highly magnified view of melanoma tumours growing in the skin. CD169+ macrophages are shown in green and yellow forming a biological boundary wall to contain the tumours.

Fig. 2 Skin CD169+ macrophages suppress B16-F10 melanoma growth.

Fig. 4 Skin CD169+ macrophages ingest tumor cells.

Scientists uncover hidden sex differences in the human immune system

Amazing stuff!

"... Now, researchers have discovered over 1,000 genetic switches that operate differently in female and male immune cells, driving higher overall activity of inflammatory pathways in females. ...

Advances in single-cell technologies now allow researchers to study individual immune cells in great detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.

The team sequenced over 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1,000 healthy individuals. ... These participants were part of the OneK1K cohort, a major Australian project designed to map how genetics influence individual immune cells at a population scale.

The analysis revealed distinct cellular profiles between the sexes.

Males had higher proportions of monocytes, cells that act as first immune responders, and their genetic activity was more concentrated on basic cellular maintenance and protein-building functions.

In contrast, females possessed higher levels of immune cells called B cells and regulatory T cells, with genetic activity heavily skewed towards inflammatory pathways.

“While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases. On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers,” ..."

From the abstract:

"Sex has a key role in disease susceptibility (in particular, autoimmunity).

Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors.

However, the cellular-level factors influencing sexual dimorphism are not fully understood.

We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts.

Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas 

male DEGs were enriched for ribosomal-related functions.

While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes.

When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus.

Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline."

Scientists uncover hidden sex differences in the human immune system | Garvan Institute of Medical Research "The study maps over a million cells to help explain why women are more prone to autoimmune diseases like lupus."

The impact of sex on the immune system explored at the single-cell level (open access)

Figure 1 Overview of study

Figure 2 Distributions of cell-type proportions across sex

Figure 3 Sex-differential expression

Researchers rethink the aging brain’s immune system, immune cells from the body flow into the brain

Amazing stuff!

"Contrary to longstanding belief, immune cells from the rest of the body flow into the brain as it ages, a finding that could open new paths for treating neurodegenerative disease."

"In brief

• Stanford scientists discovered that immune cells in the blood travel into the central nervous system.
• The discovery upends conventional wisdom that the immune systems of the brain and the rest of the body are walled off from each other.
• The researchers built on recently developed genetics tools to trace the origins of immune cells in the brain.
• The discovery suggests researchers could one day engineer peripheral immune cells to travel to the brain to treat or prevent neurological diseases.

..."

From the abstract:

"Microglia are the resident macrophages of the central nervous system. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis.

The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells contribute to the human microglial pool in certain individuals.

Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain.

Applying this approach to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals.

Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool.

Analysis of human cohort data demonstrates a protective association between most types of clonal hematopoiesis and Alzheimer’s disease.

In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which contributes to the pool of human microglia and becomes common with aging."

Stanford Report

Researchers rethink the aging brain’s immune system | Stanford Report "A discovery from an unusual team of computer scientists and pathologists overturns longstanding dogma and could point the way toward new therapies for neurodegenerative disease."

Somatic mutations reveal the ontogeny of microglia in human aging (no public access)

Somatic mutations reveal the ontogeny of human microglia (preprint, open access)

Breakdown of immune cells' interaction is key driver in aging and the liver is a major source

Good news!

"Two immune cell types’ contact plays a major role in aging. Blocking a hormone’s influence on one of those cell types halted mice’s age-associated decline in multiple organs."

"... A study in mice and human cells by Stanford Medicine researchers pins much of the blame on a particular type of immune cell's increasing inability, with advancing age, to gobble up another immune cell type. ...

So-called tissue-resident macrophages appear to be central coordinators of age-related organ decline. Blocking a single receptor on these cells preserved the youthfulness of multiple organs in mice including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone known to cause inflammation and pain in humans as well as mice.

In mice, selectively disabling this receptor exclusively on tissue-resident macrophages prevented chronic-inflammation-driven disorders of age including frailty, excessive fat accumulation and heart trouble; it also substantially slowed cognitive decline ...

Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE2, can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface.

Of the various subtypes of receptors for PGE2, one designated EP2 is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.

Infection, injury and toxic chemicals including the ones produced by our aging bodies increase PGE2 output. As the 2021 Nature paper showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages. ...

bioengineered a mouse in which, at a time of the scientists’ choosing, the gene that’s a recipe for EP2 gets deleted — but only in tissue-resident macrophages. The subsequent disappearance of EP2 from these cells, the new study proves, reinvigorated the neutrophil-devouring process that PGE2 undermines. ...

older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (their “teenage” years).

The scientists identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver.

“The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” ... “It’s the central organ determining the body’s metabolic rate.”

Smoldering senescent neutrophils, the study showed, accumulated in normal old mice’s livers, spleens and bone marrow — and, to a lesser extent, in all the many other bodily organs the researchers looked at.

But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.

EP2 deletion reduced inflammation in the blood, liver, colon, heart, kidney and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance and forelimb grip strength resembled that of young animals.

Reducing EP2 action in older mice also preserved their memory capabilities. They could thread their way through a maze or recall previously encountered objects almost as well as younger mice — and far better than similarly old mice in whose tissue-resident macrophages EP2 remained functional. ..."

From the abstract of the Perspective:

"Human aging is asynchronous. Cells, tissues, and organs deteriorate at different rates, an unevenness that may help explain the differential aging trajectories of people.

Elucidating both the overlapping and distinct biological pathways that contribute to cell-tissue-organ aging could guide strategies to promote health longevity. ...

Tan et al. (1) report that the oxylipin prostaglandin E2 (PGE2) undermines the capacity of tissue-resident macrophages (TRMs) from clearing out old, and hence damaging, neutrophils in aging organs. 

n a mouse model, this housekeeping process can be restored if PGE2 action is blocked. The implication is that organ aging is not fixed but may be shaped by specific interventions that slow the decline."

From the editor's summary and abstract:

"Editor’s summary

Increased inflammation is associated with aging and is implicated in decreased function in aging tissues.

Tan et al. explored changes in older tissue-resident macrophages and investigated how these cells may contribute to aging phenotypes in mice ... 

They found that signaling by the lipid messenger prostaglandin E2 was increased in these cells. In various mouse tissues, preventing an increase in tissue-resident macrophages helped to maintain mitochondrial function and limited other deleterious effects of aging. Tissue-resident macrophages help to reduce inflammation by removing apoptotic and damaged cells.

One consequence of inhibiting prostaglandin E2 signaling was restored clearance of senescent neutrophils. These results emphasize the possible roles of macrophages and neutrophil clearance in tissue disfunction during aging.  ...

Structured Abstract

INTRODUCTION

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear.

Tissue-resident macrophages (TRMs), long-lived cells that comprise 60 to 90% of macrophages in major organs, maintain homeostasis through efferocytosis of apoptotic and senescent cells.

Neutrophils, the most abundantly produced and shortest-lived leukocytes (more than 100 billion generated daily in humans), require continuous TRM clearance; uncleared aged neutrophils release proteases and extracellular traps that damage tissues and propagate aging. TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging. Whether impaired TRM efferocytosis drives the accumulation of senescent neutrophils that promote organ aging and whether inhibition of EP2 signaling can restore this process, remain unknown.

RATIONALE

We studied aged mice in which EP2 signaling on TRMs was selectively reduced, either genetically (TRM-specific EP2 deletion) or pharmacologically, to define how TRM dysfunction shapes organ-wide aging.

TRMs are long-lived gatekeepers of tissue homeostasis, and EP2 offers a tractable target because its activity increases in aged macrophages and suppresses their metabolic and phagocytic function.

Using complementary genetic and pharmacological approaches, we tested whether restoring TRM function reverses organ aging and identified which efferocytic substrate is most affected. The same design also defined the molecular step at which EP2 acts within TRMs and extended our findings to aged human tissues.

RESULTS

In aged mice, TRM-specific EP2 deletion restored mitochondrial fitness and immune homeostasis, and reversed cognitive decline, frailty, sarcopenia, adiposity, and cardiac dysfunction toward youthful states.

Plasma proteomics identified the liver as a major source of age-associated immune changes.

Single-cell RNA-seq of mouse liver and multiorgan flow cytometry revealed accumulation of senescent CXCR4+ neutrophils across efferocytic organs in aging. These cells exhibited the senescence-associated secretory phenotype (SASP), DNA damage response activation, cell cycle inhibitor induction, NETosis, and anti-apoptosis programs, and were efficiently cleared following EP2 deletion. Liver multiplex imaging localized paracrine stress to parenchymal cells neighboring senescent neutrophils.

Ex vivo efferocytosis assays showed that aged TRMs were most impaired in clearing senescent neutrophils relative to apoptotic substrates, with both functions restored by EP2 deletion or pharmacologic antagonism.

Mechanistically, EP2 signaling suppressed integrin-dependent stabilization of senescent neutrophils on TRMs and downstream engulfment.

Analyses of human liver and heart datasets revealed conserved EP2 up-regulation in aged TRMs, enrichment of senescent neutrophils, and reduced TRM–neutrophil interactions.

CONCLUSION

This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration. With age, neutrophils acquire senescence-associated features, and their accumulation drives tissue injury through two converging mechanisms: intrinsic degranulation and NETosis, and extrinsic paracrine stress on neighboring parenchymal cells. Pharmacological inhibition of EP2 restores TRM efferocytic capacity and promotes clearance of senescent neutrophils, positioning EP2 antagonism as a tractable therapeutic strategy for age-related organ and functional decline."

Breakdown of immune cells' interaction is key driver in aging, study finds

Breakdown of immune cells’ interaction is key driver in aging, study finds (original news release)

Tidying up aging organs (Perspective, no public access)

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging (no public access)

Tissue-resident macrophage (TRM) clearance of senescent neutrophils is restored by EP2 deletion or inhibition to limit organ aging.

The road to virtual immune cells

Good news!

"The idea of building a ‘digital twin’ of a cell that mimics its behaviour is not new, but the advancement of artificial intelligence and the rapid expansion of biological datasets is helping to make it a reality.

Capturing the activity of immune cells — and their ability to sense, interpret and respond to the environment — in this way could help reveal the intricacies of their responses and help design immune-based medicines.

In translational research, virtual immune cells could help find drug targets, improve the ability to modulate the immune system and support personalized therapies, write a group of pathologists and systems biologists."

Nature Briefing: Translational Research

Toward mechanistic virtual immune cells (no public access)

Towards Autonomous Mechanistic Reasoning in Virtual Cells (a subject related preprint by other authors)

Flatworms reveal explosive new type of immune cell

Amazing stuff!

"In brief

• ... scientists uncovered a new type of cytotoxic cell called “ruptoblasts” in experiments with planarian flatworms.
• Unlike common blood-derived immune cells, ruptoblasts are specialized gland cells that undergo an explosive cell death called "ruptosis” when triggered by a specific hormone.
• A single ruptoblast can kill dozens of target cells within minutes through an explosion of toxic agents that quickly dissipate.
• Ruptosis is the most explosive form of cell death known to date, making it distinct from all previously described cell death pathways.

... scientists have discovered a new type of immune cell that kills surrounding cells via explosion – a cellular detonation so fast and complete that the cell vanishes within minutes, leaving no trace behind. This discovery comes from an unlikely source: planarian flatworms. ..."

From the highlights and abstract:

"Highlights

• Ruptoblasts are a cytotoxic glandular cell type likely conserved across bilaterians

• Activin triggers explosive ruptosis via ER calcium amplified through the cytoskeleton

• Ruptoblasts drive tissue rejection in planarian chimeras and aid bacterial clearance

• Ruptosis releases potent broad-spectrum cytotoxic agents

Summary

Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells—T cells, natural killer cells, and neutrophils.

Here, we identify “ruptoblasts,” a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, “ruptosis,” triggered by activin, a multifunctional hormone acting as an inflammatory cytokine.

Excessive activin—induced through protein injection, genetic chimerism, or bacterial infection—initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating nearby cells, bacteria, and even mammalian cells within minutes.

Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions.

Mechanistically distinct from known cytotoxic and cell death mechanisms, the explosive nature of ruptosis relies on endoplasmic reticulum (ER)-derived calcium and cytoskeleton-dependent signal amplification.

Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations."

Flatworms reveal explosive new type of immune cell | Stanford Report "The discovery that hormonal triggers cause “ruptoblast” cells in flatworms to detonate and destroy surrounding cells within minutes could inspire new ideas in medical science."

Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense (no public access)

Graphical abstract

Scientists uncover hidden sex differences in the human immune system or e.g. why women are more prone to autoimmune diseases

Good news!

"... Now, researchers have discovered over 1,000 genetic switches that operate differently in female and male immune cells, driving higher overall activity of inflammatory pathways in females. ...

Until recently, technological limitations meant that immune differences between the sexes were studied using bulk blood analysis, which measures the average activity across a whole mixture of cells, masking specific cell behaviours. Advances in single-cell technologies now allow researchers to study individual immune cells in great detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.

The team sequenced over 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1,000 healthy individuals. ...

The analysis revealed distinct cellular profiles between the sexes.

Males had higher proportions of monocytes, cells that act as first immune responders, and their genetic activity was more concentrated on basic cellular maintenance and protein-building functions.

In contrast, females possessed higher levels of immune cells called B cells and regulatory T cells, with genetic activity heavily skewed towards inflammatory pathways. ...

they discovered that the vast majority of these variations reside on autosomes – the shared non-sex chromosomes – identifying over 1,000 sex-specific genetic switches in these regions.

Importantly, these genetic controls were linked directly to autoimmune conditions. The team found specific variants affecting the female-biased expression of two genes associated with systemic lupus erythematosus, potentially helping to explain why lupus is nine times higher in women compared to men. ..."

From the abstract:

"Sex has a key role in disease susceptibility (in particular, autoimmunity). Sex differences in the immune system originate from genes and their interactions with both intrinsic and extrinsic factors. However, the cellular-level factors influencing sexual dimorphism are not fully understood.

We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts. Female-biased sex-differentially expressed genes (sex-DEGs) in multiple immune cells were involved in tumor necrosis factor alpha (TNF-α) signaling, whereas male DEGs were enriched for ribosomal-related functions. While cis-expression trait quantitative loci (eQTLs) were less common on sex chromosomes, we identified over 1,000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes.

When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression of FCGR3A in natural killer (NK) cells (rs2099684) and ITGB2 in monocytes (rs760462), both of which are associated with systemic lupus erythematosus.

Our work reveals biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline."

Scientists uncover hidden sex differences in the human immune system | Garvan Institute of Medical Research "The study maps over a million cells to help explain why women are more prone to autoimmune diseases like lupus."

The impact of sex on the immune system explored at the single-cell level (open access)

Graphical abstract

Figure 1 Overview of study

Figure 3 Sex-differential expression