A major limiting factor in the success of immunotherapy is tumor infiltration by CD8+ T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8+ T cells. Our data reveal that P-selectin binding and expression of the retention integrin, very late antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8+VLA-1+ tumor-infiltrating lymphocytes (TILs) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue-resident memory T cells (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1+ TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1+ TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy.
Keywords: CD103; VLA-1; cancer vaccines; melanoma; tissue-resident memory T cells.