Targeting Pros1 to improve chemotherapy efficacy and immune anti-tumor response 2309304
TL;DR
A novel mechanism through which cancer cells promote Pros1 expression in response to chemotherapy is identified, and a better understanding of the mechanisms that regulate Pros1 expression may allow us to increase the efficacy of conventional therapies in melanoma patients.
Abstract
Resistance to chemotherapy is a major challenge in the treatment of advanced melanoma. Targeting the innate immune response to improve chemotherapy efficacy is a promising yet understudied area. We identified Pros1 as an innate immune checkpoint utilized by tumors to suppress the macrophage pro-inflammatory response. Secreted Pros1 prevents macrophage response to tumor damage-associated molecular patterns (DAMPs) released during chemotherapy. However, the effect of Pros1 on other immune system cells and the molecular mechanism that triggers its expression remain unclear. To determine how Pros1 affects chemotherapy efficacy and immune activation, we generated a melanoma cell line (B16F10) lacking Pros1 using CRISPR-Cas9 and tested it in a syngeneic murine preclinical model. Immune infiltration was assessed by single-cell RNA-seq in end-stage tumors. Mice bearing Pros1-deficient tumors showed a 63±10% (mean ± SEM) decrease in tumor growth after cisplatin treatment and a 5-fold increase in immune infiltration when compared to wild type. B cells were the most enriched group in Pros1-deficient tumors, with increased communication with T cells. Using bulk RNA-seq, we determined that Ifnγ stimulates Pros1 expression in melanoma cells as well as other immune suppressors, including Ido1, Pd-l1 and Tgfb1. Ifnγ-dependent Pros1 expression was conserved among several cancer cell types, including melanoma, lung, breast, and pancreatic cancer, suggesting its role as a global immune suppressor. By using siRNA, we determined that Ifngr1/Ifngr2 and Stat1 are key modulators of Ifnγ-dependent Pros1 expression, but not Stat3. We identified a novel mechanism through which cancer cells promote Pros1 expression in response to chemotherapy. A better understanding of the mechanisms that regulate Pros1 expression may allow us to increase the efficacy of conventional therapies in melanoma patients. NIH grant R01CA262241 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)