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

Abstract

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.

Keywords: biomarkers; immunotherapy; programmed cell death 1 receptor; tumor; tumor microenvironment.

Figure 1

Canonical programmed cell death 1 (PD-1) signaling in CD8 T cells. By engagement with its ligands, including PD-L1 or PD-L2, PD-1 is phosphorylated at immunoreceptor tyrosine-based switch motif (ITSM) tyrosine residue sites, which leads to the binding of SHP2. Recruited SHP2 directly downregulate T cell receptor (TCR) signaling via dephosphorylation of proximal signaling elements, including PI3K, RAS and PKC, leading to decreased activation, proliferation, cytokine production and survival of CD8⁺ T cells. In addition, PD-1 signaling increases the expression of basic leucine zipper transcriptional factor ATF-like factor (BATF), which affects differentiation of immune cells. APC, antigen-presenting cell; ITIM, immunoreceptor tyrosine-based inhibitory motif.

Figure 2

Role of non-canonical programmed cell death 1 (PD-1) signaling in tumorous Treg. PD-1 signaling inhibit proliferation and suppressive activity of tumorous Fr-II Tregs, while inhibiting IFN-γ production of tumorous Fr-III Tregs. In tumor, the major Treg population is Fr-II Treg. Thus, blockade of PD-1 signaling boost Fr-II Treg by promoting its proliferation and suppressive activity and potentially leads to hyperprogressive disease (HPD). IFN, interferon.

Figure 3

Non-canonical programmed cell death 1 (PD-1) signaling in tumorous B cells. Hepatocellular carcinoma (HCC) factors induce PD-1^high B cells through TLR4-driven Bcl-6 upregulation. By engagement with PD-L1, non-canonical PD-1 signaling in B cells inhibits antitumor immunity by enhancing IL-10 production. PD-1 blockade decreases interleukin (IL)-10 production and promotes proliferation and differentiation into a memory phenotype of B cells, which may influence efficacy of PD-1 blockade therapy.

Figure 4

Multifaceted roles of non-canonical programmed cell death 1 (PD-1) signaling in tumor cells. In malignant melanoma, hepatocellular carcinoma and pancreatic cancer, non-canonical PD-1 signaling promotes proliferation of cancer cell via interacting with mTOR and Hippo signaling. In non-small cell lungcarcinoma (NSCLC), non-canonical PD-1 signaling inhibits proliferation of cancer cell via suppressing AKT and ERK signaling. ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif.

Figure 5

Expression of PDCD1 in cancer cell lines. PDCD1 mRNA expression (RNA-seq, RPKM) data of cancer cell lines (Cancer Cell Line Encyclopedia, Broad, 2019) were downloaded from cBioPortal (https://portals.broadinst-itute.org/ccle/) in 27 March 2020. PDCD1 expression of epithelium-transformed cancer was analyzed. Note: breast cancer cell line (DU4475, RPKM=48.02668) was not included in our panel as it would make this panel less informative.

Figure 6

Tumor microenvironment (TME) characterized by canonical or non-canonical programmed cell death 1 (PD-1) signaling. Based on the different status of PD-1 signaling, we classified TME into two types: canonical PD-1 signaling-enriched TME (left) and non-canonical PD-1 signaling-enriched TME (right). Canonical PD-1 signaling-enriched TME is characterized by high infiltration of CD8 T cells and conventional CD4 T cells. Biomarkers for PD-1 blockade therapy including PD-L1 and TMB may work optimally in this type TME. However, biomarkers for non-canonical PD-1 signaling-enriched TME remains largely unknown. DC, dendritic cell; NK, natural killer; TAM, tumor-associated macrophages.