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PD-1 blockade: It’s what’s for dinner

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Science Immunology  02 Jun 2017:
Vol. 2, Issue 12, eaan8155
DOI: 10.1126/sciimmunol.aan8155

Abstract

Tumor-associated macrophages limit the efficacy of programmed cell death 1 (PD-1) blockade through an FcγR-dependent clearance mechanism.

Resistance to cancer therapy is most often conceived as a tumor cell–intrinsic process, which involves the emergence of adaptive somatic genetic alterations or transcriptional programs. In the realm of cancer immunotherapy, for example, loss-of-function alterations in genes such as JAK1, JAK2, and B2M have all been recently implicated in mediating resistance to programmed cell death 1 (PD-1) blockade. Much less is understood, however, about the role of the tumor microenvironment in mediating resistance to immunotherapy.

In a recent paper, Arlauckas et al. report an important role for tumor-associated macrophages in limiting the efficacy of PD-1 blockade. Using intravital microscopy of dorsal skinfold window chambers in immunocompetent mice inoculated with a murine colon carcinoma cell line (MC38), the authors studied the trafficking of fluorescently labeled anti–PD-1 antibodies in vivo. As expected, the authors observed anti–PD-1 antibodies within the tumor bed shortly after infusion and found these antibodies were predominantly bound to PD-1 on intratumoral T cells. Upon re-imaging 24 hours later, however, the authors made the interesting observation that a substantial portion of the anti–PD-1 antibody had been transferred from the T cell population to tumor-associated macrophages. Subsequent functional studies showed that macrophage clearance of anti–PD-1 antibody from the T cell surface was mediated by an FcγRIIB/III-dependent mechanism, which involved interactions with the Fc-portion (IgG2a) of the anti–PD-1 antibody used in the study. Disruption of these interactions led to prolonged binding of the anti–PD-1 antibody to tumor-infiltrating T cells and potentiation of tumor clearance in the MC38 mouse model. The authors also observed FcγR-dependent clearance of nivolumab from human CD8+ T cells by macrophages in vitro.

Although the relevance of the proposed mechanism within the microenvironment of human tumors remains to be seen, these findings suggest that the on-target lifespan of anti–PD-1 antibodies on tumor-infiltrating T cells may be shorter than generally appreciated. Accordingly, as the authors point out, the findings should inform efforts to develop second generation checkpoint inhibitors, which could be designed to have optimized Fc-regions that mitigate FcγR-dependent clearance and prolonged binding to tumor-infiltrating T cells.

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