The future of cancer immunotherapy: microenvironment-targeting combinations

Abstract

Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.

Fig. 1. Schematic diagram of the interaction between indirect modifiers of the tumor microenvironment and direct tumor modifiers.

Direct tumor modifiers act on tumor cells to promote cellular death. These strategies include chemotherapy, radiation therapy, targeted therapies, and epigenetic agents. Indirect modifiers operate predominantly to shift the microenvironment to favor anti-tumor immunity. This can be achieved by enhancing the efficacy or quantity of effector T cells and APCs and/or inhibiting tolerogenic cells such as Tregs and MDSCs. Indirect modulators may also alter the microenvironment through modification of the gut microbiome, the local vasculature, the cytokine milieu, or by altering cellular metabolism, including of amino acids, glucose, and lipids. As depicted, these mechanisms do not operate in isolation, as modification of the microenvironment may enhance direct tumor cell killing and vice versa.