PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

Abstract

PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment.

Figure 1

Mechanisms of action of the PD-L1 and PD-1 pathway. Tumor cells, APCs, and other cells express high levels of PD-L1. Engagement of PD-L1⁺ cells with T cells may induce T-cell apoptosis, anergy, functional exhaustion, or IL-10 production.

Figure 2

Proposed potential response biomarkers of PD pathway blockade. Several biomarkers including high levels of PD-L1 expression, Th1-type chemokines, infiltrating T cells, mutations, low levels of immune suppressive elements, and EMT/stem-like features may be associated with an active response to PD pathway blockade.

Figure 3

Mechanisms of poor tumor T cell infiltration. Active tumor β-catenin inhibits CCL4 expression and limits CD103⁺ DC recruitment and CD8⁺ T cell activation. Th1-type chemokines CXCL9 and CXCL10 are repressed by EZH2 and DNMT-mediated epigenetic silencing. Consequently CD8⁺ T cells poorly infiltrate tumor.

Figure 4

Scientific rationales of potential therapeutic combinations with PD pathway blockade. Multiple layers of immunosuppressive mechanisms, weak T cell activation, tumor intrinsic biological pathways contribute to cancer progression and therapy resistance. The different combinations with PD pathway blockade may yield a synergistic or additive clinical response.