PD-1 receptor outside the main paradigm: tumour-intrinsic role and clinical implications for checkpoint blockade

Area of Science:

• Immunology and Oncology
• Cancer Biology
• Molecular Signaling

Background:

• Immune checkpoint inhibitor (CI) antibodies targeting programmed cell death protein 1 (PD-1) on T lymphocytes are central to cancer immunotherapy success.
• Recent findings indicate PD-1 expression and signaling within cancer cells themselves, suggesting non-canonical roles.
• Tumor-intrinsic PD-1 signaling has been observed across various cancers, including melanoma, hepatocellular, lung, and colorectal cancers.

Purpose of the Study:

• To explore the emerging paradigm of tumor-intrinsic PD-1 signaling.
• To clarify the dualistic, potentially pro- or anti-tumorigenic functions of PD-1 within cancer cells.
• To understand the implications of these findings for anti-PD-1 antibody-based cancer therapies.

Main Methods:

• Review of existing literature on PD-1 expression and function in cancer cells.
• Analysis of studies investigating the impact of tumor-intrinsic PD-1 on chemoresistance and disease relapse.
• Synthesis of evidence regarding the opposing roles of PD-1 as either tumor-promoting or tumor-suppressive.

Main Results:

• Evidence suggests PD-1 can play a pro-tumorigenic role, contributing to chemoresistance and tumor recurrence.
• Conversely, other studies indicate PD-1 may exert tumor-suppressive functions.
• The precise functional role of PD-1 in cancer cells is not yet conclusively defined.

Conclusions:

• The dual role of tumor-intrinsic PD-1 signaling has significant implications for interpreting clinical responses to anti-PD-1 antibodies.
• Therapeutic blockade of PD-1 might have opposing effects: inhibiting tumor-promoting PD-1 or inadvertently blocking tumor-suppressive PD-1.
• Further research is needed to elucidate the composite roles of PD-1 and guide the development of targeted clinical strategies.