The SUV39H1/2-H3K9me3 epigenetic pathway regulates T cell effector function in colon tumor liver metastasis 3531

Abstract Description Patients with the microsatellite stable (MSS) subset of colorectal cancer, which accounts for 85-90% of all human colorectal cancer cases, do not respond to PD-(L)1 inhibitor immunotherapy. Metastasis accounts for over 90% human colorectal cancer mortality and liver metastasis accounts for 90% of human colorectal cancer metastasis. One of the mechanisms underlying Cytotoxic T lymphocyte (CTLs) effector dysfunction in the tumor microenvironment is the deregulation of the SUV39H1-H3K9me3 epigenetic pathway. Using a spontaneous mouse MSS colon tumor liver metastasis model (MCTLM), we observed that anti-PD-1 immunotherapy does not induce CTL activation in the liver metastases and exhibits no significant efficacy in suppression of liver metastasis. CTL adaptive transfer increased accumulation of the tumor-specific CTLs in liver metastasis, but also exhibited no significant efficacy in suppression of liver metastasis. However, pharmacological inhibition of SUV39H1 with F5446 significantly suppressed liver metastasis. In vitro CTL effector function RNA-seq analysis revealed that F5446 increased expression of genes linked to cell senescence, suggesting F5446 may reinvigorate CTLs during exhaustion. Our findings determine that colon tumor cells suppress tumor-specific CTL activation and function in the liver metastasis microenvironment and targeting the SUV39H1-H3K9me3 epigenetic mark is a promising treatment for suppression of MCTLM. Funding Sources Supported by NIH 1R01CA278852; VA I01CX001364; Genprix Inc. GPEX0001 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)