Consensus nomenclature for CD8+ T cell phenotypes in cancer

Abstract

Whereas preclinical investigations and clinical studies have established that CD8⁺ T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8⁺ T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8⁺ T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8⁺ T cell immunity, leading to the emergence of dysfunctional CD8⁺ T cells. The existence of different types of CD8⁺ T cells in cancer calls for a more precise definition of the CD8⁺ T cell immune phenotypes in cancer and the abandonment of the generic terms "pro-tumor" and "antitumor." Based on recent studies investigating the functions of CD8⁺ T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8⁺ T cells in cancer.

Keywords: CD8+ T cells; IFNγ; anergy; anticancer immunity; cytotoxicity; effector; exhaustion; senescence; stemness.

Figure 1.

CD8⁺ T cell phenotypes in the tumor microenvironment. (a) Effector CD8⁺ T cells that undergo terminal differentiation are characterized by low IL-2, strong IFNγ and TNFα release as well as high expression levels of the transcription factors Eomes and Id2. They do not express the surface markers CD62L, CCR7, CD27 but express killer cell lectin-like receptor G1 (KLRG-1) and PD-1.^, While terminal effector CD8⁺ T cells exhibit strong cytolytic functions in vitro, their anticancer activity in vivo is limited because of their inability to self-renew compared to stem-cell like memory CD8⁺ T cells. (b) Dysfunctional CD8⁺ T cells are characterized by cocomittant expression of two or more inhibitory receptors such as CTLA-4, PD-1, Lag-3, Tim-3, and BTLA. These cells exhibit defects in cytotoxicity, proliferative capacity, and secretion of pro-inflammatory cyotkines: IL-2, TNFα and IFNγ. (c) Senescent CD8⁺ T cells express killer cell lectin-like receptor G1 (KLRG-1) and CD57 but not CD27 or CD28. They are characterized by short telomeres, poor proliferative capacity and activation of DNA damage response (DDR) genes. These cells were also shown to express PD-1 in chronic lymphocytic leukemia patients. Senescent CD8⁺ T cells lack cytotoxicity, and were shown to express the proinflammatory mediators Il6 and Il8 in lung cancer tissue.

Figure 2.

Features of stem-cell like CD8⁺ T cells. Stem-cell like memory CD8⁺ T cells share many phenotypic features with naïve T cells (reviewed in ⁹⁷). They typically express the CD45RA phosphatase, the lymph node homing molecules CCR7 and CD62L as well as the costimulatory receptors CD27 and CD28. These cells express the transcription factors Id3 and Tcf7, secrete IL-2 and low levels of TNFα or IFNγ. These cells also have the ability to self-renew and exhibit potent anticancer responses in vivo.