Editors' ChoiceCancer

Working for Tip(DC)s

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Science Translational Medicine  05 Oct 2016:
Vol. 8, Issue 359, pp. 359ec160
DOI: 10.1126/scitranslmed.aai8747

Adoptive cell therapy (ACT) reintroduces high-affinity, antigen-specific T cells into a host for direct eradication of tumor cells. It can produce substantial clinical responses, even though tumor microenvironments present multiple barriers to immune function. The success of ACT in a subset of patients indicates that, at least under certain conditions, the tumor microenvironment might permit the cytotoxic function of infiltrating T cells. Marigo et al. tested the hypothesis that ACT induces a “helper” population of myeloid cells that positively feed back on T cell function and are required for optimal therapeutic efficacy.

Arginine metabolism is a key inhibitory pathway in tumor microenvironments, and it is regulated by arginase 1 (ARG) and nitric oxide synthase 2 (NOS2). Surprisingly, the authors demonstrated that deletion of host NOS2, but not ARG, actually reduced the efficacy of experimental ACT in preclinical tumor models. After ACT, tumors accumulated a population of antitumor myeloid cells, termed Tip-DCs [tumor necrosis factor (TNF) and NOS2-prsoducing inflammatory dendritic cells], in a CD40-CD40L–dependent manner. Intratumoral transfer of mouse or human Tip-DCs into mice with a NOS-deficient background improved survival after ACT, indicating that NOS2 production from Tip-DCs is sufficient to enhance ACT efficacy in mice. Interestingly, Tip-DC accumulation depended upon tumor antigen load and T cell affinity. Inhibition of colony, stimulating factor–1 receptor (CSF-1R) prevented tumor infiltration of immunosuppressive ARG-expressing macrophages but had no effect on tip-DCs and, as a result, enhanced the efficacy of ACT. In human colorectal cancer, high expression of CD40LG, NOS2, and TNF consistently correlated with enhanced T cell presence and improved survival over tumors relative to those that scored low for all three genes.

This study provides a model showing how high-affinity, antigen-specific T cells induce accumulation of “helper” myeloid cells that positively feed back on T cell function. As such, this work suggests that host preconditioning through myeloid reprogramming—shifting the balance from suppressive macrophages to activating Tip-DCs—might be a viable strategy to further enhance ACT efficacy in the clinic.

I. Marigo et al., T cell therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 377–390 (2016). [Full Text]

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