Combination therapy targeting soluble MIC and CTLA-4 in a transgenic adenocarcinoma mouse model improved the antitumor effect of anti-CTLA-4 therapy by increasing the functional potential of dendritic cells and antigen-specific CD8+ T cells, while also alleviating anti-CTLA-4-induced colitis.
Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (soluble major histocompatibility complex I chain-related molecule), on the therapeutic outcome of anti-CTLA4 antibody using an MIC transgenic spontaneous TRAMP (transgenic adenocarcinoma of the mouse prostate)/MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. CanCure LLC, Everett, WA 98208, USA. (2) School of Medicine, Univers
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. CanCure LLC, Everett, WA 98208, USA. (2) School of Medicine, University of Missouri, Columbia, MO 65211, USA. (3) School of Medicine, University of Missouri, Columbia, MO 65211, USA. (4) School of Medicine, University of Missouri, Columbia, MO 65211, USA. (5) Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. (6) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Cancer Immunology Program, Hollings Cancer Center, Charleston, SC 29425, USA. (7) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Cancer Immunology Program, Hollings Cancer Center, Charleston, SC 29425, USA.
