Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

Abstract

Cancer immunotherapies targeting immune checkpoints such as programmed cell-death protein 1 (PD-1) and its ligand programmed cell-death 1 ligand 1 (PD-L1), are revolutionizing cancer treatment and transforming the practice of medical oncology. However, despite all the recent successes of this type of immunotherapies, most patients are still refractory and present either intrinsic resistance or acquired resistance. Either way, this is a major clinical problem and one of the most significant challenges in oncology. Therefore, the identification of biomarkers to predict clinical responses or for patient stratification by probability of response has become a clinical necessity. However, the mechanisms leading to PD-L1/PD-1 blockade resistance are still poorly understood. A deeper understanding of the basic mechanisms underlying resistance to cancer immunotherapies will provide insight for further development of novel strategies designed to overcome resistance and treatment failure. Here we discuss some of the major molecular mechanisms of resistance to PD-L1/PD-1 immune checkpoint blockade and argue whether tumor intrinsic or extrinsic factors constitute main determinants of response and resistance.

Keywords: biomarkers; immune checkpoint blockade; immunotherapy; programmed cell-death 1 ligand 1; programmed cell-death protein 1; tumor-extrinsic resistance; tumor-intrinsic resistance.

Figure 1

Molecular structures of PD-1 and PD-L1. The domain organization of PD-1 is shown on top, with each domain indicated. The domain organization of PD-L1 is shown below, with each domain indicated.

Figure 2

PD-1 signaling pathways in T cells. The figure schematically summarizes the direct and indirect T cell inhibitory signaling mechanisms as indicated.

Figure 3

Schematic summary of cancer-intrinsic characteristics influencing clinical responses to PD-L1/PD-1 blockade therapies. The figure depicts the interaction of a T cell with a cancer cell, highlighting cancer cell intrinsic factors that can inactivate T cell activities, as indicated by the arrows.

Figure 4

The figure schematically represents tumor-extrinsic mechanisms contributing to response or resistance to PD-L1/PD-1 blockade therapies. The figure depicts on top a T cell interacting with a cancer cell, and the effects caused by the tumor microenvironment (TME) are boxed below. These include the recruitment of immunosuppressive cells as indicated, the expression of immunosuppressive metabolites and the induction of alternative immune checkpoints on the T cell.