Colorectal cancers with microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) often mutate Human Leukocyte Antigen (HLA) class I molecules, preventing detection by CD8 T cells and limiting the immune response. Nonetheless, a significant number of these patients respond well to treatment. A growing number of studies have shown that Gamma-Delta (γδ) T cells play a pivotal role in mediating the clearance of tumors with antigen-presenting cell (APC) pathway defects, including β2-microglobulin (B2M) mutations leading to HLA class I loss(1). Cancer patients with high levels of tumor-infiltrating γδ T cells have been shown to have better survival across different cancer types(2). These immune cell subsets have natural tropism for the tumor microenvironment and upon activation, can elicit rapid innate-like immune responses and orchestrate other tumor-infiltrating immune cells for tumor cell killing. Unlike αβ T cells, the activation of γδ T cells are not restricted by human leukocyte antigen (HLA) molecules. We have previously shown the T-cell receptor (TCR)-dependent activation of Vγ9Vδ2+ T cells via the sensing of accumulated phosphoantigens in tumor cells is mediated by B7 immunoglobulin family-like butyrophilin 2A1 (BTN2A1)/BTN3A1 molecules(3). Additionally, γδ T cells can be activated by other stress-inducible ligands presented by tumor cells. Here, we report on the comprehensive multispectral immunohistochemistry analysis of primary tumor tissue from 198 colorectal cancer patients using tumor tissue microarrays (TMAs). We investigated HLA class I loss, CD3+ T cells, γδ T cells, and the expression of immune checkpoint receptor, PD-1 within the tumor microenvironment. Findings from our study may have important implications for future γδ T cell tumor immunotherapy development.