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.