Table 1.

T-cell states in cancer

T-cell compartment	Subpopulation	Phenotype/signature genes	Function	Other remarks
Memory T cells (reduced overall clonal expansion)	Stem cell memory T cells19	TCF1 IL7R CD62L CCR7	Display increased proliferative capacity and mediate superior antitumor responses compared with known memory populations	Do not exhibit tumor-specific localization Retain the ability to regenerate a vast progeny of effector cells
	Central memory T cells20	TCF1 IL7R CCR7	Express lymph node homing receptors and lack immediate effector function, but efficiently stimulate DCs and differentiate into CCR7− effector cells upon secondary stimulation
	Effector memory T cells20	TCF1 IL7R CD62L	Express receptors for migration to inflamed tissues and display rapid production of IFN-γ and immediate effector function
Exhausted T cells (highly clonotypically expanded)17	TPEX	PD1 CTLA4 LAG3 TOX CD62L TCF1	Are early dysfunctional T cells A subset of predysfunctional (or “transitional”) T cells is defined by high expression of GZMK Lack effector functions	Can self-renew and differentiate and are a reservoir of TEX cells Are often found in lymph nodes and TLS Responsible for immunotherapy efficacy
	TEX	PD1 CTLA4 LAG3 TIM3 CD39 TOX CXCL13 BCL2L11	Have impaired cytotoxic function (gradually lose effector functions)	Even if terminally differentiated, TEX can proliferate in an antigen-dependent fashion
	Tissue-resident memory–like TEX	CD103 HOBIT (ZNF683)	Represent a continuum in the spectrum of TIL phenotypes Have high cytotoxic potential Express high levels of inhibitory molecules	Likely reflect a variation of TEX differentiation in the TME
	NK-cell receptor–positive TEX	CD8 KLRG1 CD57 Bcl2 LAG3	Are dysfunctional (ie, have reduced cytotoxicity against autologous AML blasts)	Are more abundant in R/R AML but can also be detected in mice with LCMV infection, in which they may be dependent on the transcription factor Zeb221,22
Stress response state (TSTR)23	Both CD8+ and CD4+ T cells	Stress-related heat shock genes (HSPA1A, HSPA1B); NF-κB signaling molecules	Are highly correlated with IFN-response CD4+ and CD8+ T-cell subsets	Are detectable in situ in the TME across various cancer types (especially those with aggressive phenotypes) Have a potential role in immunotherapy resistance

Intratumoral T cells are characterized by a remarkable phenotypic and functional diversity. This gradient of T-cell states has been described mostly for CD8⁺ TILs residing along a continuum of dysfunction.^17,24 The current status of CD4⁺ T cells in cancer has been reviewed elsewhere.²⁵ HOBIT, homologue of BLIMP1 in T cell; TCF1, T-cell–specific transcription factor 1; T_EX cells, terminally exhausted T cells; TILs, tumor-infiltrating lymphocytes; TIM3, T-cell immunoglobulin mucin receptor; TLS, tertiary lymphoid structures; TOX, thymocyte selection–associated high mobility group box protein.