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 1

PNT makes tumor cells resistant to CTL-mediated lysis.

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PNT makes tumor cells resistant to CTL-mediated lysis. (A) NO donor (1 h...
(A) NO donor (1 hour pre-treatment with 1 mM SIN-1) inhibited killing of EL-4 cells subsequently washed and loaded with specific peptides (SP) by CTLs in chromium release assay. CP-EL-4 cells loaded with control peptide. (B) Pre-treatment of EL-4 cells with 0.1 mM PNT for 10 minutes inhibited killing of target cells by CTLs. In A and B, 3 experiments in duplicate were performed with similar results. Mean ± SEM of 1 experiment is shown. (C) Killing of EL-4 cells that were labeled with 2 doses of CFSE (high and low) and pre-treated with 0.1 mM PNT by CTLs. After washing EL-4 cells were loaded with a SP (high dose) or CP (low dose). Target cells were mixed at 1:1 ratio and were incubated with OT-1 T cells for 5 hours. Data are representative results of 3 experiments. Mean ± SEM of 3 experiments *P < 0.05. (D–F) Experiments were performed as described in A–C, except that EL-4 target cells were first loaded with SP or CP and then treated with SIN-1 or PNT. (D and E) Three experiments in duplicate were performed, with similar results. Mean ± SEM of 1 experiment is shown. (F) Cumulative data (mean ± SEM) of 3 experiments are shown. (G–I) Experiments were performed essentially as described in A–C, except that EG-7 cells were used as targets instead of peptide-loaded EL-4 cells. (G and H) Three experiments in duplicate were performed, with similar results. Mean ± SEM of 1 experiment is shown. (I) Cumulative data (mean ± SEM) of 3 performed experiments are shown. *P < 0.01.