2. Academic Validation
  3. Mutant KRAS Drives Immune Evasion by Sensitizing Cytotoxic T-Cells to Activation-Induced Cell Death in Colorectal Cancer

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

  • Adv Sci (Weinh). 2023 Jan 4;e2203757. doi: 10.1002/advs.202203757.
Huashan Liu 1,  Zhenxing Liang 1,  Sijing Cheng 1 2,  Liang Huang 1,  Wenxin Li 1,  Chi Zhou 3 4,  Xiaobin Zheng 1,  Shujuan Li 5,  Ziwei Zeng 1 6,  Liang Kang 1
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, P. R. China.
  • 2 School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, P. R. China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 4 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 5 Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China.
  • 6 University Clinic Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany.
PMID: 36599679 DOI: 10.1002/advs.202203757
Abstract

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-κB 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.

Keywords

activation-induced cell death; immune evasion; mutant KRAS.

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