Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy?

Abstract

Antibody blockade of the PD-1/PD-L1 pathway has elicited durable antitumor responses in the therapy of a broad spectrum of cancers. PD-L1 is constitutively expressed in certain tumors and host immune cells, and its expression can be induced or maintained by many factors. The expression of PD-L1 on tumor tissues has been reported to be positively correlated with the efficacy of anti-PD-1/PD-L1 therapy in patients. However, multiple clinical trials indicate that patients with PD-L1-negative tumors also respond to this blockade therapy, which suggests the potential contribution of PD-L1 from host immune cells. Recently, six articles independently evaluated and verified the contributions of PD-L1 from tumor versus non-tumor cells in various mouse tumor models. These studies confirmed that PD-L1 on either tumor cells or host immune cells contributes to tumor escape, and the relative contributions of PD-L1 on these cells seem to be context-dependent. While both tumor- and host-derived PD-L1 can play critical roles in immune suppression, differences in tumor immunogenicity appear to underlie their relative importance. Notably, these reports highlight the essential roles of PD-L1 from host myeloid cells in negatively regulating T cell activation and limiting T cell trafficking. Therefore, comprehensive evaluating the global PD-L1 expression, rather than monitoring PD-L1 expression on tumor cells alone, should be a more accurate way for predicting responses in PD-1/PD-L1 blockade therapy in cancer patients.

Keywords: Cancer immunotherapy; Host immune cells; Immune evasion; Immune therapeutic effect; PD-1/PD-L1 blockade; PD-L1.

Fig. 1

PD-L1 on either tumor cells or host immune cells is proposed to function in preventing T cell-mediated tumor killing. PD-1 is highly expressed in exhausted effector T cells. PD-L1 is constitutively expressed in some tumors and host immune cells, and its expression can be induced or maintained by many factors. PD-1-PD-L1 interaction drives T cell dysfunction, which results in a weaker tumor killing ability in effector T cells. Therefore, anti-PD-1/PD-L1 antibodies-mediated specific blockade of the PD-1/PD-L1 pathway can enhance antitumor immunity

Fig. 2

Multiple experimental approaches through genetic deletion of PD-L1 on tumor cells or the hosts can be employed to elucidate the contribution of PD-L1 in mediating tumor evasion. a PD-L1-sufficient or PD-L1 knock out (KO) tumor cells are inoculated into WT immunocompetent hosts, and the source of PD-L1 contributed to tumor escape is determined by the regression of PD-L1-deficient tumors. b WT tumors are inoculated into WT or PD-L1-deficient hosts, and the source of PD-L1 contributed to tumor escape is determined by the tumor regression in PD-L1 KO hosts. c, d PD-L1-KO tumors are inoculated into WT host (c), or WT tumors are inoculated into PD-L1 KO hosts (d), and the source of PD-L1 contributed to tumor escape is determined by the therapeutic effects of anti-PD-L1 antibody

Fig. 3

A comprehensive understanding of PD-L1 on both tumor cells and immune cells in working concretely to contribute to anti-PD-L1 blockade mediated therapeutic effects. PD-L1 expressed on either tumors or host immune cells contributes to the inhibition of T cell activation, which can be released through blocking PD-L1 signaling by antibodies. During antitumor immune responses, antigen-presenting cells (APCs, especially dentritic cells and macrophages) uptake tumor antigens and activate T cells inside tumors. PD-L1 blockade on both APCs and tumor cells within the tumor microenvironment enhances T cell activation. APCs with up-taken tumor antigens migrate from the tumor tissues to the peripheral lymphoid organs to activate T cells outside tumors. Peripherally activated tumor-specific effector T cells infiltrate into the tumor sites and immunologically eliminate tumors. Peripheral PD-L1 signaling in draining lymph nodes may significantly hamper the antitumor immune responses by limiting effector T cell trafficking. Thus, PD-L1 blockades both inside and outside tumors may jointly promote host immunity to achieve effective therapy. Therefore, PD-L1 expression on either tumors or immune cells could be predictive of sensitivity to therapeutic agents targeting the PD-1/PD-L1 axis. Teff, effector T cell