Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer

Abstract

Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways is a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to Food and Drug Administration-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy and results of single-agent ICB clinical trials, and summarize the predictors of response and resistance.

Keywords: CTLA-4; PD-1/PD-L1; cancer; immune checkpoint; immunotherapy.

Figure 1

T cell activation and the role of immune checkpoints. A. General schema of T cell activation (see text for additional details). Signal 1 is provided by the TCR binding to the antigen presented on MHC. Signal 2 is the costimulation of the T cell by the interaction of CD28 on the T cell with CD80 or CD86. Cytokines act as a Signal 3 that directs the T cell differentiation. B. Mechanistic summary of TCR activation and points of CTLA-4-mediated (red) and PD-1-mediated (blue) inhibition.

Figure 2

Factors that influence response of tumors to immune checkpoint blockade. A. Tumor intrinsic markers of response to therapy, focusing on increased mutation and expression of PD-L1 by tumor cells. B. Tumor microenvironmental factors that influence response. Increased activated T cells lead to IFNγ that drives PD-L1 expression on other cells. Increased Tregs can suppress anti-tumor immune response.

Figure 3

Systemic factors that influence response to immune checkpoint. Factors can be divided into immune cells in the peripheral blood associated with better responses, HLA genotypes, and gut microbiome. Increased activated CD4 and CD8 T cells in the peripheral blood have been reported in responders. In addition, HLA diversity and HLA-B44/HLA-DR have been associated with better response. Recent reports of gut microbiome influences on ICB have made it an emerging predictive correlate for immunotherapy.