期刊
CLINICAL CANCER RESEARCH
卷 20, 期 24, 页码 6439-6451出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-3409
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资金
- NIH National Institute of Dental and Craniofacial Research [5R03DE021741-02]
- National Cancer Institute [1K08CA154963-01A1]
- NIH [P30 AI036211, P30 CA125123, S10 RR024574]
- Flow Cytometry Shared Resource Facility at the Icahn School of Medicine at Mount Sinai
- Cytometry
- Cell Sorting Core at Baylor College of Medicine
Purpose: Expression of inducible nitric oxide synthase (iNOS) in different cellular compartments may have divergent effects on immune function. We used a syngeneic tumor model to functionally characterize the role of iNOS in regulation of CD4(+)FOXP3(+) regulatory T cells (Treg), and optimize the beneficial effects of iNOS inhibition on antitumor immunity. Experimental Design: Wild-type (WT) or iNOS knockout mice bearing established MT-RET-1 melanoma were treated with the small-molecule iNOS inhibitor L-NIL and/or cyclophosphamide alone or in combination. The effect of iNOS inhibition or knockout on induction of Treg from mouse and human CD4(+) T cells in ex vivo culture was determined in parallel in the presence or absence of TGF beta 1-depleting antibodies, and TGF beta 1 levels were assessed by ELISA. Results: Whereas intratumoral myeloid-derived suppressor cells (MDSC) were suppressed by iNOS inhibition or knockout, systemic and intratumoral FOXP3(+) Treg levels increased in tumor-bearing mice. iNOS inhibition or knockout similarly enhanced induction of Treg from activated cultured mouse splenocytes or purified human or mouse CD4(+) T cells in a TGF beta 1-dependent manner. Although either iNOS inhibition or Treg depletion with low-dose cyclophosphamide alone had little effect on growth of established MT-RET1 melanoma, combination treatment potently inhibited MDSC and Treg, boosted tumor-infiltrating CD8(+) T-cell levels, and arrested tumor growth in an immune-dependent fashion. Conclusions: iNOS expression in CD4(+) T cells suppresses Treg induction by inhibiting TGFb1 production. Our data suggest that iNOS expression has divergent effects on induction of myeloid and lymphoid-derived regulatory populations, and strongly support development of combinatorial treatment approaches that target these populations simultaneously. (C)2014 AACR.
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