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T-cell exhaustion

Confidently known

  • human mouse Response to PD-1 blockade depends on a Tcf1+PD-1+ CD8+ stem-like progenitor pool, not on reinvigoration of terminally exhausted effectors. Siddiqui 2019 (Immunity)1 established in mouse tumor models that ablation of the stem-like subset abolishes ICI efficacy. Sade-Feldman 2018 (Cell)2 validated the TCF7-high vs TCF7-low CD8 axis in human melanoma scRNA-seq + IF. This reframes why a heavily PD-1+ infiltrate is insufficient without the stem-like compartment.
  • mouse TOX is the master transcription factor of the exhausted chromatin state (Alfei 2019 Nature3 and concurrent work). Necessary and sufficient to program the exhaustion transcriptome and epigenome; induced via NFAT2 and acts feed-forward. Exhaustion is chromatin-fixed.
  • human mouse The "release the brakes" framing is an oversimplification. Early PD-1 blockade models implied that blocking PD-1 "reactivates" exhausted effector cells. The TCF7/stem-like progenitor work makes it clearer that the operative mechanism is proliferative expansion of the progenitor pool, not reactivation of terminally differentiated effectors.

Human-study evidence

Study N Feature Effect 95% CI / p Method
Sade-Feldman 2018 n=48 (checkpoint-blockade-treated melanoma; 16,291 immune cells sequenced) TCF7⁺ stem-like vs dysfunctional CD8⁺ T-cell state response direction TCF7⁺ CD8 frequency associated with response (validation cohort) — scRNA-seq + IF validation

Contradictions / surprises

  • mouse TOX ablation impairs both exhaustion and T-cell persistence. The initial hope that TOX antagonism could reverse exhaustion therapeutically has been tempered: TOX-deficient CD8+ cells fail to persist under chronic antigen and die faster. TOX is more accurately a cell-intrinsic survival/differentiation program under chronic antigen than a simple brake on effector function. Direct "drug TOX" strategies should be approached carefully.
  • human mouse Exhaustion is not a single state. Progenitor / transitional / terminal subsets have distinct biology (Miller 2019 Nat Immunol and related). Clinical biomarkers that sum across these subsets (e.g., bulk PD-1+ IHC) average across functionally different populations.

Human-study evidence

No human-study citations in this section.

Suspected but unconfirmed

  • human in vitro PD-1 expression on clonally expanding T cells partially protects them from restimulation-induced cell death (in vitro human primary T cells)4. PD-L1 engagement attenuates TCR/CD28 signaling and modulates pro/anti-apoptotic proteins. If replicated in vivo, would mean anti-PD-1 could in some regimes accelerate effector-T-cell attrition — a direct challenge to the release-the-brakes framing. High-priority validation target.
  • mouse T cell-intrinsic VISTA enforces CD8 dysfunction (distinct from myeloid VISTA)5; loss synergizes with anti-CTLA-4. Direct relevance to PD-1 resistance is inferred.

Human-study evidence

No human-study citations in this section.

Emerging

  • mouse KLRG1 nominated as a novel inhibitory checkpoint in anti-PD-1-resistant melanoma6. KLRG1 upregulated on CD8 T cells after checkpoint therapy; KLRG1-high TILs enriched in anti-PD-1-refractory tumors. A novel anti-human KLRG1 mAb reduces tumor progression in humanized KLRG1 knock-in mice via combined CD8, NK, and γδ-T effects. Mechanistically distinct from the established PD-1/CTLA-4/LAG-3/TIM-3 set.
  • mouse M2 TAM-derived PGE2 drives TIGIT upregulation on PD-1+ CD8 T cells in MSS colorectal cancer7, creating terminally exhausted PD-1+TIGIT+ cells and blunting anti-PD-L1. COX2 inhibition, PGE2 receptor antagonism, or TIGIT blockade each restore activity preclinically. Specific combinatorial rationale for an indication where PD-1 monotherapy has consistently failed.
  • human Anti-TIM-3 (TQB2618) + anti-PD-1 penpulimab achieves 52% ORR in PD-1-pretreated classical Hodgkin lymphoma8 (n=21 phase Ib). Salvage signal in a setting where re-engaging checkpoint biology was not expected to yield substantial response.

Human-study evidence

Study N Feature Effect 95% CI / p Method
Hong 2026 n=21 (phase Ib (NCT05400876), PD-1-pretreated relapsed/refractory cHL) anti-TIM-3 TQB2618 + anti-PD-1 penpulimab ORR 52% (1 CR, 10 PR); grade ≥3 TRAE 24% — phase Ib clinical trial

Practical takeaways

  • A heavily PD-1+ infiltrate by IHC is not automatically a good prognostic marker — without stem-like progenitor cells, the proliferative response to blockade can be muted.
  • The field's post-PD-1 checkpoint pipeline — LAG-3, TIGIT, TIM-3, and now KLRG1 — is adding real options, though most remain investigational.

  1. Siddiqui 2019 Immunity. Link. ↩

  2. Sade-Feldman 2018 Cell. Link. ↩

  3. Alfei 2019 Nature TOX. Link. ↩

  4. PD-1 RICD protection 2026. Link. ↩

  5. T-intrinsic VISTA 2026. Link. ↩

  6. KLRG1 2026. Link. ↩

  7. TAM-PGE2-TIGIT MSS CRC 2026. Link. ↩

  8. Anti-TIM-3 + penpulimab cHL 2026. Link. ↩