Abstract B026: The senescent tumor cells evade the immune system by secreting SASPs in colorectal cancer

Abstract

Abstract In colorectal cancer, the transition of cancer cells from an adenoid to a collective invasion morphology, ultimately leading to a partial epithelial-mesenchymal transition phenotype at the invasive front, has been observed. Through comprehensive gene expression analysis, we identified distinct gene expression patterns between cancer cells at the invasive front and those in the central region, with cellular senescence playing a pivotal role in this transition. Trajectory analysis revealed a gradual transformation of non-senescent tumor cells in the central region into senescent cells at the invasive front, accompanied by altered gene expression patterns. Furthermore, we observed a progressive increase in the expression of CXCL12 and CSF1 at the invasive front. Senescent tumor cells were found to impair the directional migration of CD8+ T cells by secreting high concentrations of CXCL12. Additionally, CSF1 secreted by senescent tumor cells promoted the differentiation of monocytes into M2 macrophages, which subsequently inhibited CD8+ T cell activation. Importantly, inhibiting CXCL12 secretion from senescent tumor cells enhanced T cell infiltration and resulted in reduced tumor number and size. These findings highlight the generation of a cytokine barrier by senescent tumor cells, which serves to protect non-senescent tumor cells from immune attack. Moreover, this study identifies senescent tumor cells as a potential target for overcoming immunotherapy resistance in colorectal cancer. The development of interventions that disrupt the cytokine barrier and enhance T cell infiltration holds promise for improving the efficacy of immunotherapeutic approaches in the treatment of colorectal cancer. Citation Format: Tae Jun Park, Soon Sang Park. The senescent tumor cells evade the immune system by secreting SASPs in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B026.