Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice
Tangying Lu, … , Michael B. Sporn, Dmitry Gabrilovich
Tangying Lu, … , Michael B. Sporn, Dmitry Gabrilovich
Published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):4015-4029. https://doi.org/10.1172/JCI45862.
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Research Article Immunology

Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice

Abstract

Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloid-derived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell–associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β–expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.

Authors

Tangying Lu, Rupal Ramakrishnan, Soner Altiok, Je-In Youn, Pingyan Cheng, Esteban Celis, Vladimir Pisarev, Simon Sherman, Michael B. Sporn, Dmitry Gabrilovich

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Figure 7

Inflammation reduced the effect of adoptive T cell therapy.

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Inflammation reduced the effect of adoptive T cell therapy. (A and B) LL...
(A and B) LLC-OVA (A) or LLC-IL-1β-OVA (B) tumors were established as described in Figure 6, G and H. All mice received TBI and bone marrow transplant on day 0. OT-I T cells were transferred to the treatment groups on day 1. Data are mean ± SEM. Each group included 9–12 mice. In A the differences were significant (P < 0.01). (C and D) T cell responses. Tumor-bearing mice received TBI with bone marrow transplant and T cell transfers as described in A and B. On day 7 T cells were isolated from LNs and tumors and mixed at a 1:1 ratio with irradiated syngenic control splenocytes and stimulated with either control or specific peptides, or anti-CD3/CD28 Abs. (C) IFN-γ production was measured in ELISPOT assays. The number of spots per 5 × 104 T cells was calculated. Each experiment was performed in triplicate and included 3 mice. Cumulative mean ± SEM is shown. (D) The proliferation of T cells isolated from spleens and tumors was determined by labeling of T cells with CFSE, followed by stimulation with specific or control peptides in the presence of irradiated naive splenocytes. The experiments were performed twice, with similar results. (E and F) The percentages of MDSCs (E) and macrophages (F) in spleen and tumor sites in mice 1 week after TBI and bone marrow transfer. (G) The number of NT+ cells in LLC-IL-1β-OVA tumors 7 days after TBI. Gr-1+ cells are red; NT+ cells are brown. Scale bars: 100 μm. Right panel: Cumulative results of the number of NT+ cells per 10 high-power fields (800 × 600 μm2). Each group included 3 mice.