Sistema Gastrointestinal e Digestivo

Abstrato

The Impact of Genetic Mutation and Cytokines/Chemokines on Immune Response in Colorectal Cancer

Shenying Fang, Jiachun Lu, Xinke Zhou

Background: Systematically exploring the effect of tumor mutation and cytokines/chemokines on colon adenocarcinoma (COAD) immune response and outcome is very important and worth investigation.

Methods: We first estimated immune cell composition in 458 COAD tumors from TCGA, and then evaluated association between genetic mutation, expression of cytokine and chemokine, and immune cell subsets. Finally, we evaluated relationship between immune cell subsets, chemokines/cytokines, and patient survival.

Results: Compared to wild-type, samples with mutated tumor suppressor genes APC or TP53 had significantly lower CD8+, Neutrophil, DC, and NK cells infiltrates, while samples with mutated tumor promoter genes TTN, MUC16, or BRAF had significantly higher immune cell infiltrates. Gene expression of IFNG, TGFB1, TNF, IL6, IL10, CX3CL1, CXCL9, CXCL10 were all positively correlated with immune cell infiltrates, and inversely correlated with purity (P<0.05 after Bonferroni correction) in tumor specimens. In survival analysis, none of these chemokines or cytokines or CD8+ was significantly associated with overall survival (OS). Both increased CD4+ T and B cell subsets were associated with poorer OS in univariate analysis and in multivariable analysis after adjustment for age, sex, AJCC stage, and tumor purity (multivariable, CD4+: HR=23.49, 95% CI=1.55-356.92, P=0.023; B cell: HR=135.38, 95% CI=5.27-3480.28, P=0.003).

Conclusion: Our results suggest that genetic mutation and chemokines/cytokines were correlated with infiltration of immune killer cells and that the mutation status and inflammation biomarker expression levels could be used to select patients for immunotherapy and predict disease outcome.

Lay summary: Proportions of immune cell subsets were estimated in 458 COAD tumors from TCGA and the relationship between immune cell subsets, chemokines, and cytokines and patient survival was systematically assessed. Our study revealed significant biomarkers for tumor immune response and CRC progression.