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PathologyBiomarkerN/A (concept)

Tumour-infiltrating lymphocytes (TILs)

TILs; tumour-infiltrating lymphocytes; Clark TIL grade; "brisk", "non-brisk", "absent" TIL pattern

Tumour-infiltrating lymphocytes are an established prognostic factor in cutaneous melanoma and are increasingly recognised across other cutaneous malignancies. The classical Clark grading — brisk, non-brisk, or absent — is reported as a required item on the RCPath melanoma dataset; brisk infiltration is associated with significantly better disease-specific survival in primary melanoma cohorts. TILs are also the biological substrate for lifileucel TIL adoptive cell therapy, in which patient-specific TILs are expanded ex-vivo and reinfused. Beyond melanoma, TIL density and composition (CD8+ vs CD4+ vs FOXP3+ regulatory T cells) is being studied as a predictive biomarker for ICI response in cSCC, MCC and other skin cancers.

CurrentLast reviewed 15 May 2026

Classical Clark TIL grading

  • Brisk — TILs infiltrate the entire vertical growth phase of the tumour or are present at the base of the tumour across its full breadth.
  • Non-brisk — TILs infiltrate only focal areas of the tumour.
  • Absent — no lymphocytic infiltrate present within the invasive component.
  • Required reporting item in RCPath melanoma dataset.
  • Brisk TIL grade — independent favourable prognostic factor in localised melanoma; reduces SLN positivity risk in some series.
  • Inter-observer variability is moderate; pathology training and standardisation effort ongoing.

Prognostic and predictive significance

  • Primary melanoma — brisk TIL associated with lower SLN positivity rate and better disease-specific survival.
  • Metastatic melanoma — high TIL density at metastatic sites predicts better response to anti-PD-1 therapy.
  • cSCC, MCC — increasing evidence that high-TIL tumours respond better to ICI.
  • TIL composition matters — high CD8+ effector T-cell density predicts response; high FOXP3+ regulatory T cells predict resistance.
  • Modern digital pathology and AI-driven TIL quantification — emerging research field.

TIL therapy (lifileucel)

  • The presence of TILs within a tumour is the biological substrate for autologous TIL cell therapy — see lifileucel.
  • Surgically resected metastasis → TIL isolation → ex-vivo expansion over ~ 22 days → lymphodepleting chemotherapy → reinfusion + high-dose IL-2.
  • Lifileucel (Amtagvi) — FDA-approved (Feb 2024) for advanced melanoma after progression on anti-PD-1.
  • Objective response rate ~31% (C-144-01) in heavily pre-treated melanoma; durable complete responses in some.
  • UK access limited; specialist centres / trial / compassionate use.

Practical context

  • TIL grading is reported on every melanoma pathology specimen — discuss at MDT in relation to stage and surveillance.
  • Counsel patients with brisk TIL favourable prognosis (independent of stage).
  • Absent TIL infiltrate is a marker of immune evasion — may inform adjuvant therapy discussion.
  • TIL-rich primary tumours may yield better lifileucel manufacturing success — although clinical-trial selection has typically been by metastasis biopsy.
  • Standardisation initiatives — International TILs Working Group; reproducibility studies ongoing.

References

  1. Clark WH Jr et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst; 1989.
  2. Azimi F et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol; 2012.
  3. Chesney J et al. Lifileucel — first TIL therapy. J Clin Oncol; 2022.

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