title: Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses.
abstract: There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies.
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Woller
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Fleischmann-Mundt
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schumacher
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Knocke
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Kloos
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.affiliation: Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wirth
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.|Kreiskliniken Reutlingen, Reutlingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D007167:Immunotherapy; D064596:Isografts; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D014412:Tumor Virus Infections
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D061026:Programmed Cell Death 1 Receptor; D051193:Toll-Like Receptors