Abstract
In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.
Highlights
CD8+ T cells in the tumor immune microenvironment (TIME) are exposed to chronic antigen stimulation (Wherry and Kurachi, 2015)
As functional restoration of exhausted CD8+ T cells is important for effective antitumor immunity, advanced analytic tools (e.g., transposase-accessible chromatin using sequencing (ATAC-seq) and single-cell RNA sequencing) have been applied to identify the epigenetic characteristics and transcriptomes of exhausted CD8+ T cells to improve our understanding of cancer immunotherapy (Thommen et al, 2018; Wang et al, 2019a; Khan et al, 2019; Kim et al, 2020)
This study identifies that TI programmed cell death 1 (PD-1)+ B cells result in impairment of T cell proliferation in a PD-L1-dependent manner (Wang et al, 2019b), which suggests that TI PD-1+ B cells control antitumor immunity by directly suppressing T cell proliferation
Summary
CD8+ T cells in the TIME are exposed to chronic antigen stimulation (Wherry and Kurachi, 2015). Cancer immunotherapy using anti-PD-1 antibodies (PD-1 therapy) has been thought to enhance antitumor immunity by reinvigorating the functionality of tumor-infiltrating (TI) PD1+CD8+ T cells It has been demonstrated that PD-1 is expressed on other cells (e.g., Tregs, TAMs, and tumor cells) and that PD-1 therapy enhances antitumor immunity in a diverse cell-dependent manner (Karyampudi et al, 2016; Xiao et al, 2016; Gordon et al, 2017; Yao et al, 2018; Moral et al, 2020; Strauss et al, 2020; Zhang and Liu, 2020; Lim et al, 2021; Zha et al, 2021). TI CD8+ T cells highly express PD-1 (Wherry and Kurachi, 2015; Hashimoto et al, 2018) (Table 1)
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