Good news! Cancer is history (soon)!
"... identified a new mechanism behind the chemotherapy resistance that makes ovarian cancer so lethal.
In a new study ... the researchers showed that chemotherapy triggers an inflammatory cascade that recruits immune cells into the tumor microenvironment, which ultimately function to protect the cancer from subsequent chemotherapy. Notably, this finding could improve outcomes for patients because the molecular pathway the researchers discovered has the potential to be blocked using drugs already in clinical use for other diseases. ...
The researchers also see a possible opening for combination approaches involving immune checkpoint inhibitors, which reawaken the T cells. If T cell suppression by neutrophils turns out to be a major contributor to chemoresistance, pairing checkpoint inhibitors with IL-1β-targeted therapy could offer another route to restoring chemotherapy’s effectiveness. ..."
From the abstract (This abstract is not easy to read, too much technical jargon, written for experts only!):
"Background
High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and cell-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis.
Previous work suggests that chemotherapy induces immunological changes in the tumor microenvironment (TME). However, experimental evidence for how such chemotherapy-induced TME remodeling modulates the response to ongoing chemotherapy remains poorly documented in HGSC.
Methods
We analyzed paired pre-chemotherapy and post-chemotherapy HGSC bulk transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets to identify chemotherapy-induced tumor-extrinsic factors and their cellular sources in the TME.
To test causality, we used chemoresistant, homologous recombination-proficient murine metastatic HGSC models with deficiencies in the interleukin 1 beta (IL1β) pathway (IL1β–interleukin 1 receptor type 1 (IL1R1) axis).
Flow cytometry and scRNA-seq of omental tumors were used to define cellular interactions.
Contributions of neutrophils and neutrophil extracellular traps (NETs) were assessed by antibody-mediated depletion and immunofluorescence.
Direct effects of IL1β and NETs on cancer cell chemosensitivity were tested in vitro. Finally, paired pre-chemotherapy and post-chemotherapy omental HGSC specimens from patients were analyzed for neutrophil infiltration and NET formation.
Results
In HGSC datasets, post-chemotherapy tumors exhibited increased IL1β expression with myeloid cells identified as the primary source.
In chemoresistant murine models, chemotherapy increased neutrophils and NETs in omentum tumors in wild-type mice. These increases were abrogated in IL1β-deficient mice, which showed a shift toward an effector-like CD8+ T-cell state and improved tumor control.
Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1β-deficient mice.
In vitro, IL1β did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Furthermore, scRNA-seq and flow cytometry revealed that IL1R1 was predominantly expressed by tumor-associated fibroblasts.
Consistently, IL1R1-deficient mice exhibited increased chemosensitivity, with decreased neutrophil accumulation and increased IFNγ+TNF+CD8+ T cells. Additionally, we found that chemotherapy upregulated the neutrophil chemoattractant C-X-C motif chemokine ligand 2 (CXCL2), and disruption of the IL1β–IL1R1 axis decreased CXCL2 levels in tumor-associated fibroblasts.
Finally, residual human HGSC tumors after chemotherapy showed increased neutrophils and a trend toward increased NETs.
Conclusions
We demonstrate that chemotherapy-induced IL1β-dependent neutrophil accumulation drives chemoresistance in HGSC. This study provides experimental evidence that chemotherapy-induced inflammation contributes to chemoresistance and highlights the potential of targeting this pathway to overcome chemoresistance in HGSC."
Fig. 4 T-cell suppression and NETs may contribute to the IL1β-neutrophil-induced chemoresistance.
No comments:
Post a Comment