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

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.