When immune landscapes diverge: How immune cell heterogeneity shapes cancer immunotherapy response

Amplifying the antitumor immune response using immunotherapy has significantly improved patient survival and transformed cancer care. Findings from preclinical studies as well as clinical observations have firmly established that the intratumoral accumulation of T cells often serves as a positive predictor of immunotherapy response. While this observation has led to the commonly used “cold or hot” classifiers to describe the T cell landscape within a tumor, this is increasingly being recognized as an oversimplification. Instead, there is a growing appreciation for the broader composition, spatial localization, and dynamic nature of the tumor immune landscape across cancer types. In this perspective, we describe the diverse and unique immune correlates that have been associated with response (or lack thereof) following immunotherapy. Beginning with our own published findings related to the heterogeneous immune landscapes associated with divergent responses to adoptive T cell therapy combined with immune checkpoint inhibition, we then overlay key observations from other recently published studies to highlight the impact of the broader immune landscape in determining treatment outcome. Finally, we recommend leveraging modern multi-omic analysis tools prior to and during immunotherapy treatment to define immune signatures associated with favorable response, those that can predict treatment outcome, or which can be leveraged to identify complementary therapeutic approaches.