Overcoming Chemoimmunotherapy-Induced Immunosuppression by Assemblable and Depot Forming Immune Modulating Nanosuspension.

Abstract

The deficiency of antigen‐specific T cells and the induction of various treatment‐induced immunosuppressions still limits the clinical benefit of cancer immunotherapy. Although the chemo‐immunotherapy adjuvanted with Toll‐like receptor 7/8 agonist (TLR 7/8a) induces immunogenic cell death (ICD) and in situ vaccination effect, indoleamine 2,3‐dioxygenase (IDO) is also significantly increased in the tumor microenvironment (TME) and tumor‐draining lymph node (TDLN), which offsets the activated antitumor immunity. To address the treatment‐induced immunosuppression, an assemblable immune modulating suspension (AIMS) containing ICD inducer (paclitaxel) and supra‐adjuvant (immune booster; R848 as a TLR 7/8a, immunosuppression reliever; epacadostat as an IDO inhibitor) is suggested and shows that it increases cytotoxic T lymphocytes and relieves the IDO‐related immunosuppression (TGF‐β, IL‐10, myeloid‐derived suppressor cells, and regulatory T cells) in both TME and TDLN, by the formation of in situ depot in tumor bed as well as by the efficient migration into TDLN. Local administration of AIMS increases T cell infiltration in both local and distant tumors and significantly inhibits the metastasis of tumors to the lung. Reverting treatment‐induced secondary immunosuppression and reshaping “cold tumor” into “hot tumor” by AIMS also increases the response rate of immune checkpoint blockade therapy, which promises a new nanotheranostic strategy in cancer immunotherapy.