Regulation of tumor growth by leukocyte-specific protein 1 in T cells

Background Clinical efficacy of T cell-based cancer immunotherapy is limited by the lack of T cell infiltration in the tumor mass, especially in solid tumors. Our group demonstrated previously that leukocyte-specific protein 1 (LSP1), an intracellular signal regulator, negatively regulates T cell infiltration in inflamed tissues. Methods To determine the immuno-regulatory effects of LSP1 in T cells on tumor progression, we investigated the growth of B16 melanoma inLsp1knockout (KO) mice and T cell-specificLsp1transgenic (Tg) mice. The immune cell subpopulation infiltrated into the tumor mass as well as the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in T cells was assessed by flow cytometry and/or immunohistochemistry. Chemotactic migration was assayed withLsp1KO andLsp1Tg T cells. Adoptive transfer ofLsp1KO orLsp1Tg T cells was performed in B16 melanoma-challengedRag1KO mice. Results Lsp1KO mice showed decreased growth of B16 melanoma and increased infiltration of T cells in the tumor mass, which were completely reversed in T cell-specificLsp1Tg mice.Lsp1KO CD8(+)T cells also exhibited elevated migratory capacity in response to CXCL9 and CXCL10, whereasLsp1Tg CD8(+)T cells did the opposite. LSP1 expression was increased in tumor-infiltrating T cells and could be induced by T cell receptor activation. Intriguingly, gene expression profiling ofLsp1KO T cells suggested enhanced cytotoxicity. Indeed, expression of IFN-gamma and TNF-alpha was increased in tumor-infiltrating CD4(+)and CD8(+)T cells ofLsp1KO mice, while it was markedly reduced in those ofLsp1Tg mice. Adoptive transfer ofLsp1KO T cells toRag1KO mice was more effective in suppressing melanoma growth than transfer ofLsp1Tg T cells. Of note, when treated with antiprogrammed cell death protein 1 (PD-1) antibody, inhibition of melanoma growth was more pronounced inLsp1KO mice than inLsp1-sufficient mice, suggesting thatLsp1depletion additively increases the antitumor effects of anti-PD-1 antibody. Conclusions LSP1 in T cells regulates the growth of B16 melanoma in mice, possibly by affecting migration and infiltration of T cells into the tumor and by modulating production of antitumor effector cytokines by CD8(+)T cells. These findings provide evidence that LSP1 can be a target to improve the efficacy of T cell-based immunotherapy.