Molecular Biomarkers of Primary and Acquired Resistance to T-Cell-Mediated Immunotherapy in Cancer: Landscape, Clinical Implications, and Future Directions

The emergence of immunotherapy has revolutionized cancer treatment in recent years. Inhibitors of immune checkpoints, including antibodies against cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, and programmed death ligand 1, have demonstrated notable efficacy in certain advanced cancers. Unfortunately, many patients do not benefit from these therapies and either exhibit primary resistance to treatment or develop acquired mechanisms of resistance after initially responding to therapy. Here, we review the genomic and immune traits that may promote resistance to T-cell-mediated immunotherapy, with a focus on identifying potential biomarkers that could eventually be used in the clinical setting to guide treatment selection. We summarize the clinical evidence for these markers and discuss how current understanding of resistance mechanisms can inform future studies and aid clinical decision-making in order to derive maximum benefit from immunotherapy. Implications for Practice: Immunotherapy has rapidly progressed as a treatment modality for multiple cancers, but it is still unclear which patients are likely to benefit from these therapies. Studies of resistance mechanisms have only recently started to identify biomarkers that can help predict patient outcomes. This review summarizes the available clinical data in regard to immunotherapy resistance, with a focus on molecular biomarkers that may be useful in guiding clinical decision-making. It discusses possible applications of these biomarkers and highlights opportunities for further clinical discovery.