Inhibition of PD-1 on melanoma cells has antitumorigenic effects distinct from its role in immune cells.
Major finding: Inhibition of PD-1 on melanoma cells has antitumorigenic effects distinct from its role in immune cells.
Mechanism: PD-1 blockade reduces phosphorylation of the mTOR effector S6 in a PI3K–AKT-independent manner.
Impact: PD-1 blockade may be superior to other immunotherapies due to its dual effects on cancer and immune cells.
Antibodies targeting programmed cell death 1 (PD-1) have been successful in treating patients with melanoma. PD-1 is an immune checkpoint receptor that, upon binding to its ligands PD-L1 or PD-L2, inhibits signaling downstream of the T-cell receptor and protects tumors from immune-mediated rejection. However, melanoma cell–intrinsic PD-1 pathway effects have not been established to date. Kleffel and colleagues found that human melanomas often have PD-1–expressing subpopulations, with 22 of 36 patients having PD-1 expression in at least one of their tumor lesions. Melanoma cell–expressed PD-1 promoted melanoma tumorigenesis, even in immunocompromised mice lacking adaptive immunity. PD-1 overexpression increased the tumorigenic potential of mouse and human melanoma cells both in vivo and in vitro in the absence of immune cells, whereas PD-1 knockdown reduced melanoma growth compared with control cells. Consistent with a tumor cell–intrinsic role of PD-1 signaling in stimulating tumor growth, PD-1 increased phosphorylation of the S6 ribosomal protein in an mTOR-dependent, but PI3K–AKT-independent, manner, and increased S6 phosphorylation correlated with improved response to PD-1 therapy in patients with melanoma. Furthermore, knockdown of PD-L1 or treatment with a PD-L1 blocking antibody reversed the increased tumorigenicity of PD-1–overexpressing melanoma cells in the absence of adaptive immunity, indicating that melanoma cell PD-1 interactions with PD-L1 expressed by host and melanoma cells are required for PD-1–driven tumorigenesis. The melanoma cell–intrinsic effects of PD-1 were also confirmed using antibody-mediated PD-1 blockade; melanoma-specific PD-1 inhibition suppressed tumor growth even in immunocompromised or PD-1–deficient mice. Together, these results indicate that, in addition to its protumorigenic role in immune cells, melanoma cell–intrinsic PD-1 promotes tumorigenesis as a growth receptor that activates mTOR signaling. This finding has clinical implications, as PD-1 inhibition may be more effective than other therapies that target immune checkpoints alone.
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- ©2015 American Association for Cancer Research.