Mutant KRAS Drives Immune Evasion by Sensitizing Cytotoxic T-Cells to Activation-Induced Cell Death in Colorectal Cancer

The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8(+) T-cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti-PD-1 and adoptive T-cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS-expressing tumor cells sensitized tumor-specific cytotoxic CD8(+) T-cells to activation-induced cell death via NF-kappa B inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8(+) T-cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS-mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.

Automated summary

The study reveals that mutant KRAS plays a crucial role in tumor immune evasion in colorectal cancer. Reduced infiltration of cytotoxic CD8(+) T cells is observed in colorectal cancer specimens with mutant KRAS compared to wild type KRAS. Preclinical models confirm this finding and show poor response to anti-PD-1 and adoptive T-cell therapies in KRAS mutant tumors. Mechanistic analysis reveals that lactic acid derived from mutant KRAS-expressing tumor cells sensitizes tumor-specific cytotoxic CD8(+) T cells to activation-induced cell death through NF-kappa B inactivation, explaining the inverse association between intratumoral cytotoxic CD8(+) T cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by targeting KRAS or inhibiting lactic acid production. This study suggests the potential of targeting the KRAS-mediated immune program for the treatment of patients with KRAS mutant colorectal cancer.