Role of CD8+ T lymphocyte cells: Interplay with stromal cells in tumor microenvironment

Abstract

CD8⁺ T lymphocytes are pivotal cells in the host response to antitumor immunity. Tumor-driven microenvironments provide the conditions necessary for regulating infiltrating CD8⁺ T cells in favor of tumor survival, including weakening CD8⁺ T cell activation, driving tumor cells to impair immune attack, and recruiting other cells to reprogram the immune milieu. Also in tumor microenvironment, stromal cells exert immunosuppressive skills to avoid CD8⁺ T cell cytotoxicity. In this review, we explore the universal function and fate decision of infiltrated CD8⁺ T cells and highlight their antitumor response within various stromal architectures in the process of confronting neoantigen-specific tumor cells. Thus, this review provides a foundation for the development of antitumor therapy based on CD8⁺ T lymphocyte manipulation.

Keywords: Antitumor; CD8+ T lymphocyte; Immunosuppression; Immunotherapy; Stromal cell; Tumor microenvironment.

Graphical abstract

Figure 1

Infiltration of CD8⁺ T cells into tumors: differentiation, cytotoxicity, and dysfunction. (a) CD8⁺ T cells are programmed into CTLs after their activation and proliferation within the TME. The tumor cells are eventually eliminated, depending on IFN-γ and TNF-α secretion and apoptosis pathways. (b) Left: Various immune checkpoints in the divided region involved in CD8⁺ T cell dysfunction. Once the related ligand–receptor bindings are activated, CD8⁺ T cells are disabled and lose killing efficacy. Right: Oncologic signatures for suppressing tumor-infiltrating CD8⁺ T cells. Alternatively, WNT/β-catenin inhibits the differentiation and recruitment of CD8⁺ T cells against tumors. Other pathways include PI3K, STAT3, NF-κB, MYC, TP53, PTEN, LKB1, TOX, TCF-1, IDO, and CD39.

Figure 2

Suppressive immunization regulation of CD8⁺ T cells with stromal cells in the TME. The suppressive immunization regulation of CD8⁺ T cells for pro-tumoral microenvironment with TME-related stromal components is depicted in three parts: CAFs, TAMs, and tumor vessels. (1) For CAFs, the immune checkpoint molecules CTLA-4, TIM-3, PD-1, LAG-3, and CD73 are induced to attenuate CD8⁺ T cells. NF-κB prevents CD8⁺ T cells by upregulating CXCL12. IL-6 is secreted to downregulate CD8⁺ T cell infiltration and IL-6/STAT3 can master the PD-1/PD-L1 pathway to impair T cells by upregulating CXCR7. Tumor-specific CD8⁺ T cells are inhibited by TGF-β, along with two auto-stimulatory signaling of TGF-β and SDF-1. The CXCL12/CXCR4 axis induces FAP to diminish CD8⁺ T cells. FAS/FASL on T cells leads to CD8⁺ T cell apoptosis. CD8⁺ T cells are excluded with HDAC6 to activate STAT3 by targeting COX2. CAF-driven ROS, Chi3L1, βig-h3, and arginase II are capable of impairing CD8⁺ T cell activity. (2) For the TME, the immune checkpoint pathways PD-1/PD-L1/2 and CTLA-4/CD80/86 are observed on TAMs to confine CD8⁺ T cell initiation. NF-κB P65 is validated to impair CD8⁺ CTLs by inducing B7–H4/B7S1 and anti-apoptosis gene, as well as activating PD-1. Arginase and NO activity are modulators responsible for CD8⁺ T cell apoptosis via IFN-γ and TNF-α. IL-10 limits cytotoxic CD8⁺ T cells by suppressing DC-driven IL-12 or selectively reducing B7 upregulation. In addition, STAT1, CSF1, HLA-G, HLA-E, arginase I, and SHH from macrophages are crucial regulators to deplete the CD8⁺ T cell response. (3) During neovascularization, VEGF inhibits CD8⁺ T cell homing and induces apoptosis. HIF-1α may modulate vascularization via VEGF-A. FASL is selectively expressed in tumor-driven vasculatures to hinder CD8⁺ T cells with soluble VEGF-A, IL-10, and PGE2. NF-κB is capable of activating FASL and downregulating cFLIP for apoptosis. Intratumoral CD8⁺ T cells are rejected by RGS5, resulting in the formation of abnormal blood vessels and hypoxia. HIF-1α, ETBR, B7–H3 β-AR, PDPN, and TNF-α are also pivotal vascular molecules, impeding CD8⁺ T cell penetration into tumor sites.