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.