Reprogramming the Tumor Microenvironment to Improve Immunotherapy: Emerging Strategies and Combination Therapies

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ABSTRACT
Emerging immunotherapeutic approaches have revolutionized the treatment of multiple malignancies. Immune checkpoint blockers (ICBs) have enabled never-before-seen success rates in durable tumor control and enhanced survival benefit in patients with advanced cancers. However, this effect is not universal, resulting in responder and nonresponder populations not only between, but also within solid tumor types. Although ICBs are thought to be most effective against tumors with more genetic mutations and higher antigen loads, this is not always the case for all cancers or for all patients within a cancer subtype. Furthermore, debilitating and sometimes deadly immune-related adverse events (irAEs) have resulted from aberrant activation of T-cell responses following immunotherapy. Thus, we must identify new ways to overcome resistance to ICB-based immunotherapies and limit irAEs. In fact, preclinical and clinical data have identified abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies such as ICBs. Here, we will discuss how reprogramming various facets of the TME (blood vessels, myeloid cells, and regulatory T cells [Tregs]) may overcome TME-instigated resistance mechanisms to immunotherapy. We will discuss clinical applications of this strategic approach, including the recent successful phase III trial combining bevacizumab with atezolizumab and chemotherapy for metastatic nonsquamous non–small cell lung cancer that led to rapid approval by the U.S. Food and Drug Administration of this regimen for first-line treatment. Given the accelerated testing and approval of ICBs combined with various targeted therapies in larger numbers of patients with cancer, we will discuss how these concepts and approaches can be incorporated into clinical practice to improve immunotherapy outcomes.

PRACTICAL APPLICATIONS
Abnormalities in the TME contribute to immunosuppression and dictate the outcome of various immunotherapeutic approaches.

Reprogramming specific facets of the immune compartment, such as immunosuppressive myeloid and lymphoid cell subsets, may overcome microenvironment-induced resistance mechanisms and enhance antitumor immunity.

Targeting nonimmune components of the TME, for example, by normalizing or decompressing the vasculature, represents a clinically translatable strategy to overcoming resistance to ICBs and other immunotherapies.

A bench-to-bedside-and-back approach for microenvironment-based strategies may not only enhance immunotherapies for solid tumors but also abrogate irAEs.

Improved survival in the phase III trial combining bevacizumab with atezolizumab and chemotherapy for metastatic nonsquamous non–small cell lung cancer represents a successful example of such an approach.

https://ascopubs.org/doi/full/10.1200/EDBK_237987