Background:
Mycobacterium bovis Bacille Calmette-Guerin (BCG) is a known intralesional (ILBCG) therapeutic option for stage III in-transit/lymphatic melanoma. The mechanism of action is unknown; however, regressions in up to 50% of injected lesions and 17% of uninjected lesions have been reported. BCG and other mycobacteria express ligands capable of stimulating γ9δ2 T cells. We hypothesize that γ9δ2 T cells play a role in promoting BCG-mediated antitumor immunity in patients treated with ILBCG.
Materials and Methods:
Eight patients were diagnosed with stage III in-transit/lymphatic melanoma and treated with ILBCG per study protocol. BCG injected and uninjected lesions were resected and subjected to immunohistochemistry and RNAseq gene expression analyses.
Results:
BCG injection induced a significant increase of γ9δ2 T cell infiltration in BCG injected lesions as determined by immunohistochemistry and RNAseq gene expression analyses. Furthermore, BCG injection elicited: the expression of chemokines (such as CXCL9, 10, and 11) capable of attracting γδT cells, the expression of antigenic ligands (BTN3A1) capable of activating γ9δ2 T cells in BCG injected lesions, and the secretion of cytokines by activated γδ T cells. Interestingly, we found that γδ T cell infiltration was associated with the regression of BCG uninjected lesions.
Conclusions:
These data strongly suggest that γ9δ2 T cells contribute to in transit/lymphatic melanoma regressions induced by ILBCG. γ9δ2 T cells may serve as a useful target for future immunotherapeutic study.