The RIG-I agonist M8 triggers cell death and natural killer cell activation in human papillomavirus-associated cancer and potentiates cisplatin cytotoxicity

Author:

Girone CarloORCID,Calati FedericaORCID,Lo Cigno IreneORCID,Salvi ValentinaORCID,Tassinari ValentinaORCID,Schioppa TizianaORCID,Borgogna CinziaORCID,Lospinoso Severini LudovicaORCID,Hiscott John,Cerboni CristinaORCID,Soriani AlessandraORCID,Bosisio DanielaORCID,Gariglio MarisaORCID

Abstract

AbstractAlthough the activation of innate immunity to treat a wide variety of cancers is gaining increasing attention, it has been poorly investigated in human papillomavirus (HPV)-associated malignancies. Because these tumors harbor a severely impaired cGAS-STING axis, but they still retain a largely functional RIG-I pathway, another critical mediator of adaptive and innate immune responses, we asked whether RIG-I activation by the 5’ppp-RNA RIG-I agonist M8 would represent a therapeutically viable option to treat HPV+ cancers. Here, we show that M8 transfection of two cervical carcinoma-derived cell lines, CaSki and HeLa, both expressing a functional RIG-I, triggers intrinsic apoptotic cell death, which is significantly reduced in RIG-I KO cells. We also demonstrate that M8 stimulation potentiates cisplatin-mediated cell killing of HPV+ cells in a RIG-I dependent manner. This combination treatment is equally effective in reducing tumor growth in a syngeneic pre-clinical mouse model of HPV16-driven cancer, where enhanced expression of lymphocyte-recruiting chemokines and cytokines correlated with an increased number of activated natural killer (NK) cells in the tumor microenvironment. Consistent with a role of RIG-I signaling in immunogenic cell killing, stimulation of NK cells with conditioned medium from M8-transfected CaSki boosted NK cell proliferation, activation, and migration in a RIG-I-dependent tumor cell-intrinsic manner. Given the highly conserved molecular mechanisms of carcinogenesis and genomic features of HPV-driven cancers and the remarkably improved prognosis for HPV+ oropharyngeal cancer, targeting RIG-I may represent an effective immunotherapeutic strategy in this setting, favoring the development of de-escalating strategies.

Funder

Pasteur Research Grant

Italian Ministry for University and Research-MIUR

Associazione Italiana per la Ricerca sul Cancro AIRC

Italian Ministry for University and Research

Università degli Studi del Piemonte Orientale Amedeo Avogrado

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Immunology,Immunology and Allergy

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