Non-canonical PD-1 signaling in cancer and its potential implications in clinic

Zha, Haoran; Jiang, Ying; Wang, Xi; Shang, Jin; Wang, Ning; Yu, Lei; Zhao, Wei; Li, Zhihua; An, Juan; Zhang, Xiaochun; Chen, Huoming; Zhu, Bo; Li, Zhaoxia

Programmed cell death 1 (PD-1)-based immunotherapy has revolutionized the treatment of various cancers. However, only a certain group of patients benefit from PD-1 blockade therapy and many patients succumb to hyperprogressive disease. Although, CD8 T cells and conventional T cells are generally considered to be the primary source of PD-1 in cancer, accumulating evidence suggests that other distinct cell types, including B cells, regulatory T cells, natural killer cells, dendritic cells, tumor-associated macrophages and cancer cells, also express PD-1. Hence, the response of patients with cancer to PD-1 blockade therapy is a cumulative effect of anti-PD-1 antibodies acting on a myriad of cell types. Although, the contribution of CD8 T cells to PD-1 blockade therapy has been well-established, recent studies also suggest the involvement of non-canonical PD-1 signaling in blockade therapy. This review discusses the role of non-canonical PD-1 signaling in distinct cell types and explores how the available knowledge can improve PD-1 blockade immunotherapy, particularly in identifying novel biomarkers and combination treatment strategies.