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

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.

FIGURE 1.. The Tumor-Immune Microenvironment Mediates Tumor Progression and TreatmentResponse

The tumor-immune landscape features a collection of protumor and antitumor immune cells that promote and cooperate with other pathophysiologic features to promote the major hallmarks of cancer progression, immunosuppression, and treatment resistance. Immunotherapeutic strategies, especially involving combination therapies, must be carefully orchestrated to promote antitumor immunity for efficacious outcomes. Abbreviation: DCs, dentritic cells.

FIGURE 2.. VEGF Modulates Immune Cells to Promote an Immunosuppressive Tumor Microenvironment

Beyond its indirect ability to promote immunosuppression via an abnormal tumor vasculature, VEGF can directly influence immune cells in the tumor microenvironment and systemically by promoting immunosuppressive cells such as Tregs, MDSCs, and protumor TAMs, while inhibiting antigenpresenting cells (such as DCs and antitumor TAMs) and CTLs. Dotted gray lines indicate differentiation from iMCs to TAMs, iDCs, and MDSCs. Abbreviations: IFN, interferon; CTL, cytotoxic T lymphocyte; Treg, regulatory T cell; iDC, immature dendritic cell; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; iMC, immature myeloid cell; IL, interleukin; TGF, transforming growth factor; matDC, mature dendritic cell; DC, dendritic cell.

FIGURE 3.. Vascular Normalization Can Reprogram the Immunosuppressive Tumor Microenvironment

The abnormal tumor vasculature, induced by overexpression of VEGF, can inhibit effector T cells, preferentially recruit immunosuppressive immune cells (e.g., myeloid-derived suppressor cells [MDSCs], regulatory T cells [Tregs], and “M2-like” protumor tumor-associated macrophages [TAMs]), and promote hypoxia, thus establishing an immunosuppressive tumor microenvironment. Judicious dosing of antiangiogenic therapies (such as anti-VEGF antibodies) can reprogram the tumor microenvironment to an immunostimulatory milieu by normalizing the vasculature to facilitate T effector cell infiltration and antitumor function, reduce MDSC and Treg accumulation, and alleviate hypoxia, which can induce conversion of TAMs to an “M1-like” antitumor phenotype. Reprinted with permission from Jain.

FIGURE 4.. Adaptive Immune Responses Dictate Myeloid Cell Activity to Influence Tumor Progression

Although regulation of adaptive and innate immune responses is likely bidirectional and can be altered by treatment modalities, different adaptive cells can also promote either pro- or antitumor myeloid cell phenotype and function and together influence tumor progression. In cases where the immune response to cancer results in increased T_H1 cytokines by adaptive cells (e.g., CD4⁺ T cells and natural killer [NK] cells), this induces myeloid cell bioactivity that promotes tumor stabilization or regression. On the other hand, when the responding adaptive response includes chronic B cell, T_H2, and regulatory T-cell activation, myeloid cells upregulate programs that promote tumor progression, including angiogenesis and immunosuppression. Abbreviations: DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells.

FIGURE 5.. Mechanisms of Regulatory T-Cell Suppression in the Tumor Microenvironment

Regulatory T cells (Tregs) are able to inhibit the function of antigen-presenting cells (APCs) and T effector cells by three main mechanisms. First, Tregs support their own immunosuppressive function by consuming interleukin (IL)-2 (via the IL-2 receptor CD25). Second, Tregs inhibit APCs (via CTLA-4 binding to CD80/CD86) to downregulate costimulatory signals to T effector cells. Third, Tregs directly inhibit T effector cells and APCs with suppressive cytokines (IL-10, IL-35, and transforming growth factor [TGF]-β) or by inducing apoptosis (perforin and granzyme). Alternatively, Tregs can induce suppression by catabolizing adenosine (ADO) from ATP released by apoptotic Tregs under oxidative stress (in the hypoxic and acidic TME) via CD39 and CD79, which binds to ADO A2A receptors (A2AR) on CTLs and APCs to inhibit their function. Abbreviations: TCR, T-cell receptor; MHC, major histocompatibility complex.