The nitric oxide radical scavenger carboxy-PTIO reduces the immunosuppressive activity of myeloid-derived suppressor cells and potentiates the antitumor activity of adoptive cytotoxic T lymphocyte immunotherapy

Abstract

Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) can result in robust and durable antitumor responses. Tumor-infiltrating CTLs produce IFNγ and mediate antitumor activity, but they simultaneously induce counter-regulatory immunosuppressive mechanisms in the tumor by recruiting monocytic myeloid-derived suppressor cells (MDSCs) that limit their proliferation and effector function. Using a murine model of adoptive immunotherapy for B16 melanoma, we developed a strategy to augment CTL activity by downregulating immunosuppression by MDSCs. Intravenous injection of transgenic pmel-1 CTLs into tumor-bearing mice, resulted in their infiltration into the tumor, but this was accompanied by the accumulation of large numbers of monocytic MDSCs (M-MDSCs). These cells hampered CTL function and reduced their numbers in the tumor. We determined that one mechanism responsible for this immunosuppression was the production of nitric oxide (NO) by MDSCs in the tumor. Therefore, mice were given the NO scavenger carboxy-PTIO (C-PTIO) on the day after CTL transfer. This led to the restoration of impaired proliferative capacity and function of the CTLs, resulting in sustained suppression of tumor growth. Thus, we conclude that CTL therapy can be improved by counter-acting immunosuppression. Targeting NO, one mediator of the immunosuppressive activity of M-MDSCs, may be an appropriate strategy to restore impaired CTL function and improve the efficacy of immunotherapy.

Keywords:

• adoptive transfer
• carboxy-PTIO
• CTL
• myeloid-derived suppressor cells (MDSCs)
• nitric oxide (NO)

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

This study was supported in part by a Grant-in-Aid for Scientific Research of the Ministry of Education, Culture, Sports, Science and Technology (Kazuhiro Kakimi). The study sponsors had no involvement in study design, collection, analysis, and interpretation of data, writing the report, or the decision to submit the report for publication. The Department of Immunotherapeutics, University of Tokyo Hospital is endowed by Medinet Co. Ltd. (Yokohama, Japan).