PD-1/PD-L1 blockade increases TAM phagocytosis of tumor cells to extend survival in mouse cancer models.

  • Major finding: PD-1/PD-L1 blockade increases TAM phagocytosis of tumor cells to extend survival in mouse cancer models.

  • Concept: PD-1 expression in TAMs increases over time and is associated with disease stage in human tumors.

  • Impact: Anti PD-1/PD-L1 therapies act directly on TAMs in addition to T cells to mediate antitumor effects.

Checkpoint blockade targeting PD-1/PD-L1 has clinical efficacy in a variety of tumor types, and has been shown to function through activation of T cells. However, PD-1 is also expressed on macrophages, prompting Gordon and colleagues to investigate the effects of PD-1 blockade on macrophages in the tumor microenvironment. Fluorescence-activated cell sorting of cells from syngeneic colon cancer models revealed that approximately 50% of tumor-associated macrophages (TAM) expressed surface PD-1. In contrast, no circulating monocytes or splenic macrophages had detectable PD-1 expression. The majority of PD-1+ TAMs exhibited an M2-like surface profile, suggesting a protumor phenotypes, whereas the PD-1 TAMs were often M1-like, indicative of an inflammatory phenotype. The PD-1+ TAM population emerged approximately 2 weeks after tumor engraftment, and PD-1 expression increased over time. Consistent with these findings, TAMs from human colorectal tumors exhibited high but variable expression of PD-1, with the M2 subset exhibiting higher PD-1 expression than the M1 population. The frequency of PD-1+ M2 TAMs increased with disease stage. In mouse tumors, most PD-1+ TAMs and tumor-infiltrating lymphocytes arose from circulating leukocytes, not resident immune cells. PD-1+ TAMs displayed reduced phagocytosis of tumor cells compared with PD-1 TAMs, and PD-L1 depletion resulted in enhanced tumor cell phagocytosis by macrophages and reduced tumor size. Further, treatment with an anti–PD-1 or anti–PD-L1 antibody reduced tumor growth, even in mice lacking T cells, and the effects were abrogated by TAM depletion. Macrophages can be induced to phagocytose tumor cells via CD47 blockade, and combining anti-CD47 with anti–PD-L1 resulted in greater tumor reduction and increased survival. These findings demonstrate that PD-1/PD-L1 blockade has a direct effect on TAMs, in addition to other immune cells, and can promote tumor cell phagocytosis.

Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495–9.