The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology

Abstract

Functional, tumor-specific CD8⁺ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8⁺ effector T cell dysfunction. Among the many facets of CD8⁺ T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8⁺ T cell senescence is incompletely understood. Naïve CD8⁺ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8⁺CD28^- senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8⁺CD28^- senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8⁺ T cells could improve the efficacy of future anti-tumor immunotherapy.

Keywords: CD8+CD28− T cells; cancer; cancer immunology; glioblastoma; immunotherapy; malignant glioma.

Figure 1

The priming and inactivation of CD8⁺ T cells. The interaction between TCRs and the peptide-MHC complex is the first step toward antigen-induced CD8⁺ T cell activation. This creates a site of extensive contact between T cells and APC, also called immunological synapses, where binding of CD28 on T cells with CD80/CD86 on APCs transduces a pivotal secondary costimulatory signal to complete the priming of naïve CD8⁺ T cells. In addition, CD4⁺ T helper (Th) cells when activated by DCs acquire not only the synapse-composed MHC class II and costimulatory molecules (CD54 and CD80), but also the bystander peptide-MHC-I complex from DC and become CD4⁺ Th-APCs, resulting in direct CD4⁺ T–CD8⁺ T cell interactions and subsequently delivery of CD40L signaling to CD40-expressing CD8⁺ T cells [21]. Furthermore, CD4 Th cells also secrete cytokines, such as IL-2, which promotes the differentiation of naïve CD8⁺ T cells into effector CTLs and memory CD8⁺ T cells. CTLs destroy antigen-specific target cells (such as cancer cells or viral infected host cells) via pathways including granule exocytosis, Fas ligand, and TRAIL-mediated apoptosis leading to tumor control or virus clearance and subsequent physiological T-cell inactivation as well as memory CD8⁺ T-cell formation [33]. Whereas pathological T-cell inactivation or conversion of CTL to CD8⁺ senescent T cells leads to tumor progression and virus replication.

Figure 2

Phenotypical and molecular changes in cellular senescence. A variety of intracellular (DNA damage, oncogenes, etc.) and/or extracellular signals (oxidative stress, chronic inflammation, etc.) can induce cellular senescence. Senescent cells exhibit numerous characteristics including but not limited to cell cycle arrest, increased nuclear p16 and p21 expression, increased lysosomal SA-β-gal activity, shortened telomere, and increased lipofuscin. Senescent cells can also present as a specialized secretory phenotype termed senescence associated secretory phenotype (SASP). Of particular interest, senescent immune cells present with lowered expression of CD28 and CD27 but heightened expression of CD57, KLRG-1, TIGIT, and other NK-cell associated surface receptors.

Figure 3

The heterogeneous functions of CD8⁺CD28⁻ T cells. CD8⁺CD28⁻ T cells originate from activated CD8⁺CD28⁺ T cells or from interaction with tolerogenic APCs. CD8⁺CD28⁻ T cells exhibit both cytotoxic and immunoregulatory phenotypes and vary in pathological states such as across different cancer types or inflammatory/autoimmune conditions.

Figure 4

The many facets of C8+ T cell dysfunction. In comparison to activated effector T cells, T cell anergy, exhaustion, and senescence can be distinguished by their unique expression or lack of expression of surface receptors as well as different levels of intracellular cytokines, such as IL-2.