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

Anandi Sawant, Cara C. Schafer, Tong Huan Jin, Jaroslaw Zmijewski, Hubert M. Tse, Justin Roth, Zhihuan Sun, Gene P. Siegal, Victor J. Thannickal, Stefan C. Grant, Selvarangan Ponnazhagan, Jessy S. Deshane*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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 longterm 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.

Original languageEnglish
Pages (from-to)6609-6620
Number of pages12
JournalCancer Research
Volume73
Issue number22
DOIs
StatePublished - 15 Nov 2013
Externally publishedYes

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