Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location

To define differences in tumor microenvironment (TME) immune phenotypes between right and left colorectal cancers (CRCs) and explore their therapeutic implications. Gene expression profiling and clinical characteristics of patients with CRC were retrieved from The Cancer Genome Atlas data portal. Immune cell infiltration was estimated based on single-sample gene set enrichment analysis. CRCs tissue microarrays (TMAs) containing 90 consecutive cases of surgical samples were used for validation. Expression of CD8A and VEGFA was confirmed by immunohistochemistry (IHC) analysis with TMAs, and overall survival (OS) was analyzed. Expression profiling data demonstrated that CRC immune microenvironment from right side tumor was characterized as increased infiltration of immune cells with enhanced cytotoxic function, based on higher cytotoxic activity scores (CYT) and interferon-γ signatures. Expression of VEGFA, which could be neutralized by bevacizumab, was associated with decreased levels of activated CD8⁺ T-cells, Th1 cells, and PRF1 expression on the right side, but not on the left side. IHC analysis of TMAs further confirmed an inverse correlation between CD8A and VEGFA expression, and revealed a favorable OS for patients with CD8A^HiVEGFA^Lo disease among right-side CRCs. For the left side, higher CD56^bright natural killer cell infiltration and active 4-1BB/IFN-ɑ signaling, which could providing a favorable condition for cetuximab-mediated antibody-dependent cell-mediated cytotoxicity effect, was present in a cohort with extended OS. In the TME, features of immune phenotype sidedness were identified, providing an implication for differential responses to bevacizumab/cetuximab treatment. In addition, a new avenue for innovative experimental design and combinational immunotherapy to treat CRC patients was suggested.