Jhalak Dholakia1, Carly B Scalise1, Ashwini A Katre1, Whitney N Goldsberry1, Selene Meza-Perez2, Troy D Randall3, Lyse A Norian4, Lea Novak5, Rebecca C Arend6. 1. University of Alabama in Birmingham, Division of Gynecologic Oncology, Birmingham, AL, United States of America. 2. University of Alabama at Birmingham, Division of Immunology & Rheumatology, Birmingham, AL, United States of America. 3. University of Alabama at Birmingham, Division of Immunology & Rheumatology, Birmingham, AL, United States of America; University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America. 4. University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America; University of Alabama at Birmingham, Department of Nutrition Sciences, Birmingham, AL, United States of America. 5. University of Alabama at Birmingham, Department of Anatomic Pathology, Birmingham, AL, United States of America. 6. University of Alabama in Birmingham, Division of Gynecologic Oncology, Birmingham, AL, United States of America; University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America. Electronic address: rarend@uabmc.edu.
Abstract
BACKGROUND: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/β-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/β-catenin modulation facilitates a more immunotherapy-favorable TME. METHODS: Human tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/β-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing. RESULTS: DKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights. CONCLUSIONS: Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy. Published by Elsevier Inc.
BACKGROUND: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/β-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/β-catenin modulation facilitates a more immunotherapy-favorable TME. METHODS: Human tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/β-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing. RESULTS: DKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights. CONCLUSIONS: Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy. Published by Elsevier Inc.
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