SUN-297 RSK1/2 Are Drivers of Immune Evasion in TNBC

Abstract Disclosure: A.N. Spirrison: None. D.A. Lannigan: None. A small molecule inhibitor for the Serine/Threonine protein kinase family RSK1-4, known as PMD-026, is now in phase II clinical trials for hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. RSK1/2 are considered to be tumor agonists, while RSK3/4 are tumor suppressors. RSK1/2 knockout (KO) mice are viable whereas RSK1-4 KO mice are not. Utilization of PMD-026 in patients raises concerns due to the long-term effects of inhibiting RSK3/4 and the significance of RSK in tumor immunology being largely unknown. Intriguingly, in an in vivo, immunocompetent Triple Negative Breast Cancer (TNBC) model we found that RSK1/2 KO causes increased (∼3-fold) cluster of differentiation 4-positive (CD4+) T cell infiltration into the tumor. CD4+ T cells are able to recruit B cells to the tumor, and consistent with these observations, we observed a ∼2-fold increase in B cells into the tumor. These results are unexpected, as in both tumor-bearing and non-tumor-bearing mice there was a ∼2-fold decrease in the CD4+ T cells in the spleen and inguinal lymph nodes in the RSK1/2 KO mice. B cells were also decreased in the spleen and inguinal lymph nodes in the RSK1/2 KO mice. In melanoma, it has been observed that RSK1/2 drive immune evasion of tumor cells by decreasing cell surface expression of major histocompatibility complex (MHC) molecules. Major histocompatibility complex class II-positive (MHC-II+) tumors recruit CD4+ T cells and promote anti-tumor immunity. We hypothesize that RSK1/2 may drive immune evasion of the TNBC cells by decreasing MHC expression. In the RSK1/2 KO, there may be an increase in MHC-II+ tumor cells, thus explaining the increase in CD4+ T cells we observed. CD4+ T cells in the tumor may then recruit B cells to the site. TNBC is a highly metastatic disease with poor patient outcomes, however longer patient survival has been associated with increased CD4+ T cell tumor infiltration. Additionally, higher levels of tumor infiltrating lymphocytes e.g. B cells indicate improved response to immunotherapies, such as immune checkpoint blockades (e.g. anti-programmed death-ligand 1 (PD-L1) therapy). PD-L1 is a useful target as it is elevated in TNBC patient tissue. We hypothesize that a RSK1/2 inhibitor will work synergistically with an anti-PD-L1 therapy to increase tumor immunogenicity and improve TNBC patient survival. A RSK1/2 inhibitor may be beneficial over a pan-RSK inhibitor, e.g. PMD-026, as it specifically targets a number of known tumor agonists in TNBC. Presentation: Sunday, July 13, 2025