Abstract
The understanding of the tumor microenvironment (TME) has been expanding in recent years in the context of interactions among different cell types, through direct cell–cell communication as well as through soluble factors. It has become evident that the development of a successful antitumor response depends on several TME factors. In this context, the number, type, and subsets of immune cells, as well as the functionality, memory, and exhaustion state of leukocytes are key factors of the TME. Both the presence and functionality of immune cells, in particular T cells, are regulated by cellular and soluble factors of the TME. In this regard, one fundamental reason for failure of antitumor responses is hijacked immune cells, which contribute to the immunosuppressive TME in multiple ways. Specifically, reactive oxygen species (ROS), metabolites, and anti-inflammatory cytokines have central roles in generating an immunosuppressive TME. In this review, we focused on recent developments in the immune cell constituents of the TME, and the micromilieu control of antitumor responses. Furthermore, we highlighted the current challenges of T cell-based immunotherapies and potential future strategies to consider for strengthening their effectiveness.
Highlights
The immune cell composition is variable in different tumors, but generally includes quantitatively and functionally different populations of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloidderived suppressor cells (MDSCs), and B cells (Figure 1)
CD4+ T cells contribute to the antitumor response directly by eliminating tumors through cytolytic mechanisms mediated by the release of IFN-γ and Tumor necrosis factor (TNF)-α, and indirectly by modulating the presence and activity of immune cell infiltrates in the tumor microenvironment (TME) [154,155] (Figure 2)
It is exciting to note that even the failure of these cell-based, antibody-directed, or micromilieu-targeting novel immunotherapies is accompanied by new lessons, as well
Summary
The concept of immunosurveillance has long been debated [8,9] since the first hypothesis of immunosurveillance was formulated by Paul Ehrlich in 1909 [10]. The mechanism of MDSC-induced immunosuppression occurs at multiple levels These include production of ROS and reactive nitrogen species (RNS) [56,57] that cause T cell hypo-responsiveness and apoptosis [34,35,58], and the production and release of anti-inflammatory cytokines such as IL-10 and TGF-β, which suppress the effector immune cell functions [55,59]. The presence of NK cells in the TME correlates with good prognosis in breast cancer [73], gastrointestinal stromal tumors [74], neuroblastoma [75], prostate cancer, lung cancer [76], and in several other tumors [77,78] Despite this positive correlation in several solid tumors, many studies have revealed that tumor-infiltrating NK cells have altered expression of inhibitory and activating receptors, and overexpression of exhaustion markers [79,80], and eventually, impaired activities [81,82,83]. A deeper understanding of NK cell functions in the TME, their phenotype, intercellular communication with other constituents of the TME, and the molecular constituents of the environment need to be further elucidated
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