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Cancer Res. 2013 Nov 15;73(22):6609-20. doi: 10.1158/0008-5472.CAN-13-0987. Epub 2013 Oct 1.

Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways.

Author information

1
Authors' Affiliations: Departments of Pathology, Medicine, Microbiology, and Pediatrics, The University of Alabama at Birmingham, Birmingham, Alabama.

Abstract

Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of first-line therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term antitumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor-infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective antitumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8(+) T-cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8(+) T-cell response and further decreased regulatory T cell infiltration. For long-term antitumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively transferred memory cells responded to tumor rechallenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, to generate effector and persistent memory cells for tumor eradication, and to prevent lung cancer relapse.

PMID:
24085788
PMCID:
PMC3854493
DOI:
10.1158/0008-5472.CAN-13-0987
[Indexed for MEDLINE]
Free PMC Article

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