title: Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model.
abstract: Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 × 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 μg/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Ave, Pittsburgh, PA, 15213, USA.
authors.forename: Jyothi Thyagabhavan
authors.initials: JT
authors.lastname: Mony
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Ma
authors.forename: Shannon
authors.initials: S
authors.lastname: Grabosch
authors.forename: Tejas S
authors.initials: TS
authors.lastname: Tirodkar
authors.forename: Joan
authors.initials: J
authors.lastname: Brozick
authors.forename: George
authors.initials: G
authors.lastname: Tseng
authors.forename: Esther
authors.initials: E
authors.lastname: Elishaev
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Anda M
authors.initials: AM
authors.lastname: Vlad
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C060192:MUC1 protein, human; D018396:Mucin-1