Understanding the tumor microenvironment for effective immunotherapy

Abstract

Advances in immunotherapy have led to durable and long-term benefits in a subset of patients across a number of solid tumor types. Understanding of the subsets of patients that respond to immune checkpoint inhibitors at the cellular level, and in the context of their tumor microenvironment (TME) is becoming increasingly important. The TME is composed of a heterogeneous milieu of tumor and immune cells. The immune landscape of the TME can inhibit or promote tumor initiation and progression; thus, a deeper understanding of tumor immunity is necessary to develop immunotherapeutic strategies. Recent developments have focused on characterizing the TME immune contexture (type, density, and function) to discover mechanisms and biomarkers that may predict treatment outcomes. This has, in part, been powered by advancements in spatial characterization technologies. In this review article, we address the role of specific immune cells within the TME at various stages of tumor progression and how the immune contexture determinants affecting tumor growth are used therapeutically.

Keywords: biomarkers; immune checkpoint inhibitors; immune contexture; immunotherapy; tumor microenvironment.

Figure 1

Different roles of TME‐driven cell populations in cancer progression. Cell populations within the TME modulate immune‐activating or immunosuppressive conditions to prevent or promote tumor growth. (A) T cell effector function and differentiation signals can be supported by the dendritic cell (DC) through the interleukin‐12 (IL‐12) secretion. (B) Cancer‐associated fibroblast (CAF) plays an immunosuppressive function by inhibiting CD8⁺ T cell infiltration and function via secreting transforming growth factor‐beta (TGF‐β). (C) Within the TME, tumor‐associated macrophage (TAM) consists primarily of the M2 macrophage, which is tumorigenic. TAM (M2) contributes to angiogenesis through the secretion of vascular endothelial growth factor (VEGF). (D) CD4⁺ T cell can play immunoactivative or immunosuppressive roles through the differentiation into T helper type 1 cell (Th1) and regulatory T cell (Treg), respectively. Th1 is able to induce CD8⁺ T cell by releasing cell‐activating cytokines such as interferon‐gamma (IFN‐γ); however, Treg has an immunosuppressive activity through the inhibition of CD8⁺ T cell function via releasing IL‐10 and TGF‐β. (E) Myeloid‐derived suppressor cell (MDSC) causes suppression of tumor‐specific CD8⁺ T cell response by increasing the levels of prostaglandin E2 (PGE2) and arginase (ARG). (F) Mast cell can promote tumor progression through angiogenesis development by secreting certain proteases, such as matrix metalloproteinase 2 (MMP‐2) and MMP‐9, and also by releasing VEGF and fibroblast growth factor (bFGF) from the extracellular matrix (ECM). (G) Similar to the mast cell, neutrophil is also capable of developing angiogenesis via secreting VEGF and MMPs. (H) Natural killer (NK) cell can induce innate and adaptive immune responses through the secretion of pro‐inflammatory cytokines, including IFN‐γ, tumor necrosis factor‐alpha (TNF‐α), and granulocyte/monocyte colony‐stimulating factor (GM‐CSF). TME, tumur microenvironment [Color figure can be viewed at wileyonlinelibrary.com]