Intratumoral heterogeneity and immunotherapy resistance: clinical implications.

The impressive but incomplete clinical success of immunotherapy with immune checkpoint inhibitors makes it of paramount importance to understand and overcome immunotherapy resistance. The phenomenon of resistance to immunotherapy has been largely categorized as innate or acquired; however, many cellular and molecular mechanisms of resistance are remarkably common to both. This notion raises the possibility that resistance mechanisms develop during the coevolution of the tumor and the immune response, reflecting the multiple interactions between malignant cells and cells of the tumor immune microenvironment. This tumor-editing interaction selects for often preexisting adapted genetic or epigenetic variants, and results in intratumoral heterogeneity (ITH) within tumors and among metastatic lesions. Variants encompass both tumor-intrinsic genetically driven ('hardware') and tumor-extrinsic ('software') resistance mechanisms that dynamically coevolve under strong immune selection pressures in a Darwinian fashion. The level of ITH, which is shaped by the evolution of tumors in their immune microenvironment, may dictate the ability of tumors to adapt and evade attacks by the immune system. Standardized methods and metrics for measuring and addressing ITH and making use of this information in human cancer management remain limited, partly due to the lack of suitable models, technologies, and bioinformatic tools. Opportunities exist to design therapeutic approaches to overcome immunotherapy resistance, with an emphasis on interventions targeting intrinsic versus extrinsic resistance mechanisms in the context of ITH. These therapeutic approaches can be tailored according to the nature of the specific ongoing or predicted resistance mechanisms, as observed on a per-case basis, and may include a range of options, such as biomarker-driven rational immunotherapy combinations, novel immunoregulatory targets, and the suitable incorporation of cell-based adoptive therapies. In this review, we discuss the evidence for ITH driving immunotherapy resistance and provide a perspective on integrating ITH as a biomarker and when designing more efficacious therapeutic strategies.