INKT cell modulation of tumor microenvironment (TME) and antitumor immunity: the role of antitumorigenic and protumorigenic iNKT cells

Abstract

Abstract Preclinical and clinical data indicate that iNKT cells play important roles in antitumor immunity. High number of iNKT cells in the PBL of cancer patients usually correlates with a favorable prognosis. We found that compared to wild-type (WT) mice, depletion of iNKT cells did not affect tumor progression or metastasis in mice bearing melanoma or Lewis lung cancer; restoring iNKT cells by transferring thymocytes into iNKT KO mice dramatically enhanced antitumor immunity. The underlying mechanism is no known. Herein, we report progress on the mechanistic study. Thymocyte transfer only reconstituted iNKT cells in liver, spleen and blood, but not in LN of iNKT KO mice. This suggests that two functionally opposite iNKT subsets exist in the immune system, and thymocyte transfer only restored antitumorigenic iNKT, but not protumorigenic iNKT cells. Transferring IFNγ KO thymocytes diminished iNKT reconstitution-induced antitumor immunity; transferring IL-17A KO thymocytes enhanced iNKT reconstitution-enhanced antitumor immunity. Compared to WT mice or iNKT KO mice, iNKT reconstitution in iNKT KO mice up regulated the expression of XCL1, FLT3L and CCL5, down regulated IL-6, TGFβ1, TGFβ2, COX2 expression, increased IRF8+ cDC1 cells and Siglec F− DC, and decreased αSMA+ FAP+ cancer-associated fibroblasts (CAF) and MDSC in the tumor. Taken together, these results support that antitumorigenic iNKT cells produce IFNγ dominant cytokine and facilitate NK/cDC1 infiltration and activation in the tumor to induce antitumor immunity; protumorigenic iNKT cells induce CAF to produce TGFβ, which induces a myeloid cell-mediated inhibitory TME. The balance between antitumorigenic and protumorigenic iNKT cells shapes the TME and antitumor immunity.