Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies

Abstract

The clinical success of cancer immunotherapies targeting PD-1 and CTLA-4 has ignited a substantial research effort to improve our understanding of tumor immunity. Recent studies have revealed that the immune contexture of a tumor influences therapeutic response and survival benefit for cancer patients. Identifying treatment modalities that limit immunosuppression, relieve T cell exhaustion, and potentiate effector functions in the tumor microenvironment (TME) is of much interest. In particular, combinatorial therapeutic approaches that re-educate the TME by limiting the accumulation of immunosuppressive immune cells, such as Foxp3 regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), while promoting CD8⁺ and CD4⁺ effector T cell activity is critical. Here, we review key approaches to target these immunosuppressive immune cell subsets and signaling molecules and define the impact of these changes to the tumor milieu. We will highlight the preclinical and clinical evidence for their ability to improve anti-tumor immune responses as well as strategies and challenges for their implementation. Together, this review will provide understanding of therapeutic approaches to efficiently shape the TME and reinvigorate the immune response against cancer.

Keywords: adenosine; immune toxicity; mucosal-associated invariant T (MAIT) cells; natural killer T (NKT) cells; prostaglandin; regulatory T cells (Tregs); transforming growth factor (TGF)β; tumor-associated myeloid cells.

Figure 1

Immunosuppressive targets in the tumor microenvironment. Re-educating the tumor microenvironment to improve the response to cancer immunotherapies can be performed through targeting many cellular and immunosuppressive factors. These include (A) tumor-infiltrating myeloid cells such as tumor-associated macrophages and dendritic cells, (B) tumor-infiltrating Tregs, and (C) tumor-derived immunosuppressive factors. Therapeutically altering these immunomodulatory components may promote anti-tumor immunity either alone or synergize with FDA-approved immune checkpoint inhibition.

Figure 2

Growing challenges in the implementation of immunotherapeutic strategies. Decision-making for the most efficacious immunotherapeutic combination for cancer patients presents multiple layers of challenges. These include those surrounding the patient's tumor microenvironment, the potential risk for initiation of immunotoxicities, and the sequence for appropriate timing of therapeutic interventions. Surrounding each of these challenges are multidimensional considerations that relate to improving anti-tumor immunity and targets that influence the selection of immunomodulatory agents.