Antitumor T-cell Reconditioning: Improving Metabolic Fitness for Optimal Cancer Immunotherapy

Abstract

With the rapid rise of immunotherapy for cancer treatment, attention has focused on gaining a better understanding of T-cell biology in the tumor microenvironment. Elucidating the factors underlying changes in their function will allow for the development of new therapeutic strategies that could expand the patient population benefiting from immunotherapy, as well as circumvent therapy resistance. Cancers go beyond avoiding immune recognition and inducing T-cell dysfunction through coinhibitory molecules. Recent work has demonstrated that the tumor microenvironment elicits metabolic changes in T cells that dampen their ability to respond and that manipulating these metabolic changes can strengthen an antitumor immune response. Here we review the metabolic status of various types of T cells, the energetic state of the tumor microenvironment, and proposed modalities for improvement of immunotherapy through metabolic remodeling. Clin Cancer Res; 24(11); 2473-81. ©2018 AACR.

Figure 1. Metabolic hallmarks of the tumor microenvironment

The same tumor type can differ from patient to patient. In the TME there is a metabolic heterogeneity in terms of acidity, hypoxia and nutrient availability. These metabolic changes have an impact on the function of tumor infiltrating lymphocytes.

Figure 2. Metabolism markets as predictors for immunotherapy response

Different technical approaches currently used and in development for the analysis of the metabolic state in the TME. Assessment of the metabolic state of the tumor could predict response to immunotherapy.

Figure 3. Therapeutic strategies to enhance metabolic fitness in the TME

Different mechanisms by which T cell function could be enhanced by targeting the TME. A. Direct T cell metabolic targeting methods by enhancing mitochondrial biogenesis. B. Mechanisms to enhance T cell priming during expansion of T cells used for Adoptive Transfer and CAR T cell therapies. C. Mechanisms targeting metabolites and nutrient availability in in the TME D. Mechanisms to inhibit tumor hypoxia through oxygenation and pharmacological agents. T cell effector (Teff), memory T cells (Tm).