Wedding of Molecular Alterations and Immune Checkpoint Blockade

Genomics as a Matchmaker

Elena Fountzilas, MD, PhD; Razelle Kurzrock, MD; Henry Hiep Vo, PhD; Apostolia-Maria Tsimberidou MD, PhD


J Natl Cancer Inst. 2021;113(12):1634-1647. 

In This Article

Abstract and Introduction


The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyperprogression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. US Food and Drug Administration–approved molecular biomarkers of immunotherapy response include mismatch repair deficiency and/or microsatelliteinstability and tumor mutational burden of at least 10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (eg, ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome, those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers to optimize the implementation of precision immunotherapy in patient care.


Immunotherapies such as checkpoint inhibitors have demonstrated durable responses in selected patients with diverse tumor types. However, only about 20% of patients respond to immune checkpoint blockade, and a clinically significant proportion of patients who derive benefit from this treatment eventually develop resistance.[1] Additionally, serious immune-related adverse events have been reported in a clinically significant proportion of patients who receive checkpoint inhibitors, and others have experienced accelerated disease progression (known as hyperprogression).[2–4] It is therefore essential to identify robust biomarkers of immune checkpoint blockade efficacy to select the optimal treatment for each patient.

Programmed cell death-ligand 1 (PD-L1) expression on tumor or immune cells was the first US Food and Drug Administration (FDA)–approved immune-related biomarker, predicting response to checkpoint blockade in diverse tumor types, including non-small cell lung cancer (NSCLC), melanoma, urothelial cancer, renal cell cancer, and triple-negative breast cancer.[5] However, patients with PD-L1–negative tumors often respond to immunotherapy, and therefore PD-L1 expression as a solitary biomarker for checkpoint blockade benefit is suboptimal.

Deficient mismatch repair (dMMR)/microsatellite instability (MSI)[6,7] and intermediate-to-high tumor mutational burden (TMB) (>10 mutations/megabase [mut/mb])[8,9] predict salutary effects from checkpoint inhibitors, regardless of tumor of origin. Recently, the FDA approved these genomic alterations as pan-solid cancer immunotherapy response predictors. Current efforts and this review (Table 1)[6,8,10,12–38,40–46,48–52] are focused on the rapidly evolving field evaluating novel genomic immunotherapy biomarkers in diverse tumor types.