Abstract
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.
Highlights
CD8+ T cells have the capacity to recognize and kill tumor cells
Hierarchical clustering highlighted several analytes that were highly expressed by melanoma antigen recognized by T cells (Melan-A)-specific CD8+ effector memory T cell (TEM) cells compared with total TEM cells from either healthy donors or patients, including: CX3CR1, CD62P-ligands, CD62E-ligands, CD62L, very late antigen (VLA)-1, VLA-2, and VLA-4
Unsupervised hierarchical clustering of the expression data from this second screen showed that vaccine-induced Melan-A-specific TEM cells from melanoma patients display a homing receptor expression signature that is distinct from TEM cells derived from the blood of healthy donors or the total TEM cell pool from patient blood (Figure 1D)
Summary
CD8+ T cells have the capacity to recognize and kill tumor cells. The intensive development of T cell-based cancer immunotherapies over the past two decades has demonstrated remarkable therapeutic potential in both animal models and humans [1,2,3,4,5,6]. Complete tumor regression is seen in only a minority of patients, highlighting the need for better understanding and optimization of immunotherapeutic tools. There is significant evidence that endogenous antitumor T cell responses improve clinical outcome, provided that T cells home efficiently to tumor and are retained there [7]. Numerous groups have reported discrepancies between the chemoattractants present within solid tumors and the corresponding homing receptors expressed by tumor-specific T cells [8,9,10,11,12]
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