Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.

OBJECTIVES

Gamma-delta (γδ) T cells have been associated with favorable prognoses across several malignancies, underscoring their potential as targets for novel immunotherapies. These unconventional T lymphocytes exhibit an intrinsic tropism for the tumor microenvironment, largely driven by their capacity to recognize stress-induced antigens characteristic of metabolically dysregulated tumors. Unlike the mechanism governing conventional cytotoxic CD8+ alpha-beta (αβ) T cells, γδ T-cell receptors can engage tumor cell moieties independent of major histocompatibility complex class-I (MHC-I) and human leukocyte class-I molecules. Therefore, γδ T cells may have a pivotal role in the immune response to beta-2 microglobulin-mutated MHC-I negative (MHC-I-) colorectal cancers (CRCs) with deficient mismatch repair.

METHODS

To determine whether γδ T-cell mobilisation extends to diverse aetiologies of MHC-I loss, we used multispectral immunohistochemistry to stain 150 stage I-IV primary CRC tissues, across eight tissue microarrays.

RESULTS

Our investigation revealed MHC-I loss in ~30% of CRC primary tumors across all disease stages, with a notable increase in stromal γδ T-cell frequency and activation status among stage III cases. Importantly, these findings extend previous observations largely confined to mismatch repair-deficient CRC by demonstrating that stromal γδ T-cell enrichment associated with MHC-I loss also occurs in mismatch repair-proficient tumors, suggesting a broader role for γδ T cells in immune surveillance of MHC-I-deficient CRC.

CONCLUSION

These data highlight the potential of γδ T cells in counteracting immune evasive MHC-I- tumors, thereby offering a robust rationale for their strategic deployment in next-generation immunotherapy regimens.