Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

Abstract

Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFβ) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.

Keywords: Biomarkers; CTLA-4; Cancer; Checkpoint; Genomic; Immunotherapy; Inhibitor; PD-1; Response.

Fig. 1

Immune checkpoint blockade. Professional antigen-presenting cells activate naive T cells through MHC-II complex/TCR and B7(CD80/86)/CD28 co-stimulatory binding. CTLA-4 inhibitors prevent competitive inhibitory binding of CTLA-4 with B7 ligands, which allows for more effective T cell activation. Activated effector T cells hone in on tumor cells and release IFNγ and other cytokines which boost the anti-tumor immune response. Tumor cells express PD-L1, which inhibits immune activity by binding to T cell PD-1 receptors, despite TCR recognition of target tumor antigens presented on tumor cell MHC-1 complex. Regulatory T cells (Tregs) also inhibit T cell activity and lead to an “exhausted” effector T cell phenotype. PD-1 inhibitors and PD-L1 inhibitors enhance the anti-tumor immune response by interrupting binding between tumor cell PD-L1 ligands and T cell PD-1 receptors. CTLA-4 cytotoxic T lymphocyte-associated antigen 4, MHC major histocompatibility complex, PD-1 programmed cell death protein 1, PD-L1 programmed death ligand 1, TCR T cell receptor

Fig. 2

Pathways, genomic characteristics, and molecular mechanisms implicated in response to immune checkpoint therapy. Alterations in canonical cancer pathways such as the MAPK, PI3K, and WNT-β-catenin pathways are associated with increased resistance to ICB. Inactivation of the MAPK and PI3K pathways, through alterations such as PTEN loss, are associated with a reduction in TILs and decreased expression of pro-inflammatory cytokines in the TME. Conversely, activation of the WNT-β-catenin and IDO1 pathways results in suppression of T cells and NK cells in the TME. Genome-wide characteristics, including deficiencies in DNA repair machinery and increased tumor mutational/neoantigen burden, are also associated with resistance. Increased mutational burden has been shown to lead to an elevated neoantigen burden, which results in a highly immunogenic tumor. If the neoantigens are clonal, T cell response is capable of eradicating the entire tumor, rather than a subpopulation of tumor cells. Furthermore, decreased HLA variability, LoF alterations in the JAK-STAT pathway, and induction of TGFβ increase resistance to immune checkpoint therapy through alteration of the immune response directly. HLA human leukocyte antigen, ICB immune checkpoint blockade, IDO1 indoleamine 2,3-dioxygenase, JAK-STAT janus kinase/signal transducers and activators of transcription, LoF loss of function, MAPK mitogen-activated protein kinase, NK natural killer, PI3K phosphoinositide 3-kinase, PTEN phosphatase and tensin homolog, TGFβ transforming growth factor beta, TIL tumor infiltrating lymphocytes, TMB tumor mutational burden

Fig. 3

Immune-related features and pathways predictive of response to immune checkpoint blockade. Copy number amplifications of the JAK-2/PD-L1/2 regions, increased PD-L1 expression via an intact JAK-STAT pathway culminating in IRF-1 binding to the PD-L1 promoter, high MHC-I/II expression, and HLA variability all correlate with response to ICB. Elevated concentrations of effector and helper T cells and low concentrations of Tregs and TGFβ in the TME are also associated with response to ICB. HLA human leukocyte antigen, ICB immune checkpoint blockade, IRF-1 interferon regulatory factor 1, JAK-STAT janus kinase/signal transducers and activators of transcription, MHC major histocompatibility complex, PD-L1 programmed death ligand 1, TGFβ transforming growth factor beta, TME tumor microenvironment, Treg regulatory T cell