Recruiting T cells and sensitizing tumors to NKG2D immune surveillance for robust antitumor immune response.

Abstract

Although recruiting T cells to convert cold tumors into hot can prevent some tumors from evading immune surveillance, tumors have evolved more mechanisms to achieve immune evasion, such as downregulating major histocompatibility complex I (MHC I) molecules expression to prevent T cells from recognizing tumor-antigens, or secreting immune suppression cytokines that disable T cells. Tumor immune evasion not only promotes tumor growth, but also weakens the efficacy of existing tumor immunotherapies. Therefore, recruiting T cells while reshaping innate immunity plays an important role in preventing tumor immune escape. In this study, we constructed a long-acting in situ forming implant (ISFI) based on the Atrigel technology, co-encapsulated with G3-C12 and sulfisoxazole (SFX) as a drug depot in the tumor site (SFX+G3-C12-ISFI). First, G3-C12 could recruit T cells, and transform cold into hot tumors. Furthermore, SFX could inhibit tumor-derived exosomes secretion, reduce the shedding of NKG2D ligand (NKG2DL), repair NKG2D/NKG2DL pathway, reinvigorate natural killer (NK) cells, and evade the effects of MHC I molecules missing. In the humanized cold tumor model, our strategy showed an excellent anti-tumor effect, providing a smart strategy for solving tumor evasion immune surveillance.