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


Tumor microenvironment complexity, intratumoral heterogeneity, and distinct host immunity complicate the identification of immune checkpoint blockade predictive biomarkers. Tumors and their surrounding ecosystem have individually distinct and complex immune profiles. Biomarkers such as PD-L1, assessed by IHC, may be imprecise predictors of immune checkpoint blockade response for technical reasons or because of the complexity of the immune response.[5] In addition, overexpression of specific biomarkers, such as alternate checkpoints TIM-3 and VISTA, was also statistically significantly associated with shorter PFS after anti–PD-1- and PD-L1-based therapies in patients with diverse malignancies.[170] Therefore, patients may need customized combinations of immunotherapy. Ultimately, composite biomarkers that incorporate genomic and immune profiles, host pharmacogenome as reflected by MHC and the TCR repertoire, and other factors may be needed. Based on current data, it seems unlikely that a single biomarker will be predictive for all patients or all types of immunotherapeutic agents. Machine learning algorithms that can combine genomic, transcriptomic, epigenomic, and immune-related markers and consider their interactions may be exploitable to overcome the complexity of the immune system. Ideally, all patients with cancer should be screened for all available immuno-oncology markers and receive the corresponding best treatment. Prospective trials should focus on the systematic analysis of genomic and immune profiles of patients who are treated on immuno-oncology trials and the correlation of these profiles with response or resistance and toxicity. Given the plethora of biomarkers that have been correlated with resistance to immunotherapy, particularly hyperprogressive disease, caution is warranted when patients with these biomarkers are considered for immuno-oncology treatments. The identification of novel biomarkers and consensus regarding "molecular resistance" to immunotherapy would help optimize the deployment of these potentially curative treatments.