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Synergy between Resolvins and Immune Checkpoint Blockade in a Novel Transplantable FANCC −/− Murine Head and Neck Tumor Model
Author(s) -
Gartung Allison,
Gilligan Molly M.,
Bielenberg Diane R.,
Fishbein Anna,
Wells Susanne,
Huang Sui,
Kieran Mark W.,
Serhan Charles N.,
Panigrahy Dipak
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.496.10
Subject(s) - cancer research , medicine , head and neck squamous cell carcinoma , cancer , tumor microenvironment , immune checkpoint , fanconi anemia , immunotherapy , immunology , inflammation , immune system , head and neck cancer , biology , dna repair , biochemistry , gene
Fanconi anemia (FA) patients have increased incidence of malignancies including aggressive head and neck cancer. Traditional cancer therapies, including chemotherapy and radiation, in head and neck cancer patients with mutations in the FA pathway (e.g. FANCC −/− ) have failed and the development of novel therapeutics has been hindered by a lack of relevant pre‐clinical models. While FA knockout mice recapitulate tumorigenic properties and the stromal microenvironment, these genetic models exhibit extreme variability in time to develop invasive disease (e.g. 80–400 days), presenting a tremendous challenge to evaluate novel FA cancer therapies. Transplantable tumor systems are optimal to assess the anti‐tumor activity of new therapeutic approaches, however, few to no such models for FA have been characterized to date. Controlling inflammation is now recognized as a critical component of successful cancer treatment. While FA patients exhibit excessive inflammatory cytokines, a new direction has emerged with the discovery of endogenous omega‐3 fatty acid‐derived lipid mediators, such as resolvins, which have potent pro‐resolving activity without being immunosuppressive. These lipid autacoids act through promoting the clearance of cellular debris by macrophage phagocytosis, resulting in reduced localized pro‐inflammatory cytokines. As immunotherapy response can be predicted by DNA repair deficiencies that occur in FA, we hypothesize that stimulation of resolution of inflammation and checkpoint blockade would inhibit FANCC −/− tumor growth. Utilizing FANCC −/− and wild type (WT) murine head and neck squamous cell carcinoma cells, we have developed a robust transplantable tumor model in immunocompetent mice. FANCC −/− tumors exhibited accelerated growth and histologic findings demonstrated numerous FA tumor cells with dysplastic nuclei and Ki‐67‐positive proliferating cells compared to WT tumors. FANCC −/− tumors also expressed the immune checkpoint proteins PD1, PD‐L1, and CTLA4. Immune checkpoint blockade (e.g. anti‐PD1) and resolvins alone or in combination suppressed FANCC −/− subcutaneous and orthotopic (e.g. tongue) tumor growth and prolonged survival. Therefore, we have established a transplantable FANCC −/− murine head and neck tumor model whereby various novel therapies can be efficiently evaluated prior to clinical translation. The synergy between resolvins and immune checkpoint inhibitors to suppress FANCC −/− head and neck tumor growth provides a rationale for targeting immunotherapy and the resolution of inflammation for the treatment of FA cancers. Support or Funding Information National Cancer Institute grant RO1 01CA170549‐02; ROCA148633‐01A4; Credit Unions Kids at Heart Team. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .