Study uncovers immune switch for cancer and autoimmunity

Good news! This could be a breakthrough. Cancer is history (soon)!

"... A single signaling pathway controls whether immune cells attack or befriend cells they encounter while patrolling our bodies, researchers ... have found. Manipulating this pathway could allow researchers to toggle the immune response to treat many types of diseases, including cancers, autoimmune disorders, and those that require organ transplants. ...

The critically important building of immune tolerance to “self” is a two-step process.
The first, called central immune tolerance, occurs in the bone marrow and the thymus where B cells and T cells undergo a first round of selection to eliminate or reprogram self-reactive cells before they are released into the bloodstream.
The second, peripheral immune tolerance, serves as a backup to screen circulating cells that escape the first culling. ...

The immune system’s response – threatening or welcoming – is governed by the Tregs, which tamp down inappropriate attack impulses of other immune cells called T and B cells. ... “We not only discovered this mechanism, but we also learned how it can be turned on and off.” ...

Type 1 conventional dendritic cells, or cDC1s, specialize in engulfing dead or dying cells or pathogens and displaying bits of those cells like immunological fishing lures for T cells.

To learn how cDC1s are involved in the development of immune tolerance, ... to investigate whether and how the genes they express change in mice after total lymphoid irradiation. They found that the gene encoding the receptor for erythropoietin – EPOR, is expressed at much higher levels in the cDC1s of irradiated animals, and that the levels of EPO are elevated in the animals’ blood circulation. ...

Normally, this would have been a huge surprise. Erythropoietin is well known as the primary instigator of red blood cell production, and it was named for this function (erythro meaning “red” and poietin meaning “to produce”). But [researchers] now show that signaling through EPOR in cDC1s – the antigen-presenting cells that orchestrate T-cell responses to cell-associated antigens – acts as a central switch controlling immune tolerance.
In earlier work, the same researchers demonstrated that EPO produced by immunologically “cold” tumors can suppress antitumor immunity by acting on macrophages. Together, these discoveries establish the EPO-EPOR axis as a fundamental regulator of immune balance, extending its influence from dendritic cell-mediated T-cell programming to broader immune regulation.

When ... genetically manipulated the mice to remove the ability of the cDC1s to express the EPOR, the animals rejected transplants of unmatched tissue after total lymphoid irradiation, showing conclusively that the EPO signaling pathway is necessary for the development of immune tolerance. But there was another intriguing finding.

“What was quite a surprise to me is that when you remove or block the EPO receptor on the cDC1s, you don’t just block the development of tolerance,” ... “Instead, you have now converted these cDC1s into super stimulators, or powerful activators of immune response. There is a dual opportunity to not just induce tolerance to treat autoimmune diseases, but also to trigger a strong immune response to cancer cells or to life-threatening infections.” ..."

From the abstract:

"Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis and cross-presenting abilities, resulting in antigen-specific T cell immunity or tolerance. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown.

Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses.

In total lymphoid irradiation-induced allograft tolerance, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection.

Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum.

Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation.

EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases."

Study uncovers immune switch for cancer and autoimmunity | Stanford Report "Researchers found that a key molecule involved in red blood cell production governs whether the immune system attacks or tolerates cells, revealing potential treatments for autoimmune diseases and cancer."

Erythropoietin receptor on cDC1s dictates immune tolerance (no public access)