Jungang Liu1,2,3, Xiaoliang Huang1,2, Haizhou Liu4, Chunyin Wei1,2, Haiming Ru1,2, Haiquan Qin1,2, Hao Lai1,2, Yongsheng Meng1,2, Guo Wu1,2, Weishun Xie1,2, Xianwei Mo1,2, Caroline H Johnson5, Yawei Zhang6, Weizhong Tang7,8. 1. Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China. 2. Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China. 3. Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA. 4. Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China. 5. Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA. caroline.johnson@yale.edu. 6. Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA. yawei.zhang@yale.edu. 7. Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China. tangweizhong@gxmu.edu.cn. 8. Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China. tangweizhong@gxmu.edu.cn.
Abstract
BACKGROUND: KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. METHODS: 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated. RESULTS: NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes. CONCLUSIONS: KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.
BACKGROUND:KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. METHODS: 535 CRCpatients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRCpatients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRCpatients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRCpatients was established and validated. RESULTS: NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRCpatients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRCpatients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRCpatients with distinct clinical outcomes. CONCLUSIONS:KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRCpatients.
Authors: Cristina M Tato; Nicola Mason; David Artis; Sagi Shapira; Jorge C Caamano; Jay H Bream; Hsiou-Chi Liou; Christopher A Hunter Journal: Int Immunol Date: 2006-02-15 Impact factor: 4.823