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 |
| 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; TEX 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.