Hijacked Immune Cells in the Tumor Microenvironment: Molecular Mechanisms of Immunosuppression and Cues to Improve T Cell-Based Immunotherapy of Solid Tumors

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.

The Current Application and Future Prospects of Astragalus Polysaccharide Combined With Cancer Immunotherapy: A Review

“…DCs and T cells are both suppressed by IL-10. Meanwhile, IFN-γ, TNF-α, IL-2, and IL-1β play crucial parts in killing tumor cells according to previous researches (West et al, 2013;Garris et al, 2018;Balta et al, 2021). Furthermore, another study showed that intratumoral DC's IL-12 cytokine signaling leads to anti-tumor immunity, and the antitumor cytokines IFN-γ and IL-12 are stimulated by immunotherapy.…”

Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies

“…Finally, another molecule that is significantly involved in the generation of a pro-tumor setting is the vascular endothelial growth factor (VEGF), highly secreted by tumor cells and by pro-tumoral TAMs [ 127 , 128 , 129 , 130 ].…”

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

“…In many tumors, like colorectal cancer, breast cancer, ovarian cancer or bladder cancer, the infiltration of CD8 + CTLs is thought to be a good prognostic marker [46]. However, in large, progressed tumors, CTLs are often exhausted and dysfunctional and express high levels of exhaustion markers like PD-1, lymphocyte-activation gene 3 (LAG-3), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or TIGIT [47].…”

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