Abstract P5-17-06: P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer

Abstract

Abstract The immune suppressive tumor microenvironment (TME) in metastatic breast cancer (MBC) limits the benefits of immunotherapy with immune checkpoint inhibitors (ICIs). In particular, the primary TME drives the expansion and recruitment of immune suppressive myeloid cell populations, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Treatments targeting these populations can potentially improve the efficacy of ICI therapy. To that end, our published and new findings have revealed that the p38 Mitogen-Activated Protein Kinase (MAPK) contributes to the expansion and mobilization of TAMs and MDSCs. Further, we found that pharmacological blockade of p38 decreased metastasis and increased the levels of CD8+ T cells while decreasing TAMs in the primary TME. Depletion of PMN-MDSCs, a major MDSC subset, was accompanied by reduced TAM infiltration and phenocopied the anti-metastatic effects of p38 blockade. Next, we explored the impact of p38 blockade on the composition and functionality of the immune populations in the primary TME by using single-cell RNA-sequencing. We found that p38 blockade increased levels of Irf8+ monocytic populations, indicating a decrease in immune-suppressive properties of the TME. Notably, p38 blockade increased the expression of factors related to the activation of CD8+ cytotoxic T lymphocytes, i.e., Jchain, Icos, and Cd137. Thus, our data indicate that p38 blockade alters the immune landscape within the primary TME and favors an antitumor immune response. Our data also suggest that the p38 kinase controls the production of tumor-derived factors (TDFs) which facilitate the recruitment of those pro-tumor myeloid populations. Thus, we explored this p38-TDF-myeloid axis by using trans-well migration assays. We tested the migration of the monocyte-like cell line RAW 264.7 in response to tumor-conditioned media prepared from tumor cells treated with or without the p38 inhibitor, Ralimetinib. Our data showed that the migration of RAW 264.7 cells was significantly diminished towards the conditioned media from tumor cells treated with the p38 inhibitor or from tumor cells with a genetic inactivation of p38α by CRISPR/Cas9 compared to the corresponding controls. Altogether, our studies demonstrate that p38 kinase is a potential therapeutic target, which reshapes the immune suppressive contexture of TME in MBC to improve antitumor immunity. Citation Format: Priyanka Rajan, Justin Zonneville, Sean Colligan, Scott Abrams, Andrei Bakin. P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-06.