Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

Minu K Srivastava,^1,2 Li Zhu,^1,2 Marni Harris-White,² Min Huang,^1–3 Maie St John,^1,3 Jay M Lee,^1,3 Ravi Salgia,⁴ Robert B Cameron,^1,3,5 Robert Strieter,⁶ Steven Dubinett,^1–3 Sherven Sharma<sup>1–3

1</sup>Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, ²Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, ³Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, ⁴Department of Medicine, University of Chicago, Chicago, IL, ⁵Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, ⁶Department of Medicine, University of Virginia, Charlottesville, VA, USA

Abstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with immunotherapies. Optimization of combined approaches that simultaneously downregulate MDSC suppressor pathways, restore APC immune-stimulating activity, and expand tumor-reactive T cells will be useful in improving therapy.

Keywords: MDSCs, antigen-presenting cells, natural killer cell activation, T-cell activation, immunotherapy