Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies

Cancer Cell. 2025 Apr 14;43(4):757-775.e8. doi: 10.1016/j.ccell.2025.02.026. Epub 2025 Mar 13.

Abstract

We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.

Keywords: CTLA-4; Head and neck cancer; LAG-3; PD-1; T cell dynamics; clinical trial; combination immunotherapy; multispectral imaging; single-cell genomics; tumor immunology.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • CD8-Positive T-Lymphocytes* / drug effects
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • Female
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / immunology
  • Head and Neck Neoplasms* / pathology
  • Head and Neck Neoplasms* / therapy
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Immunologic Memory
  • Immunotherapy* / methods
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytes, Tumor-Infiltrating* / drug effects
  • Lymphocytes, Tumor-Infiltrating* / immunology
  • Lymphocytes, Tumor-Infiltrating* / metabolism
  • Male
  • Neoadjuvant Therapy* / methods
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Squamous Cell Carcinoma of Head and Neck* / drug therapy
  • Squamous Cell Carcinoma of Head and Neck* / immunology
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / therapy

Substances

  • CTLA-4 Antigen
  • Immune Checkpoint Inhibitors
  • Lag3 protein, human
  • Lymphocyte Activation Gene 3 Protein
  • Programmed Cell Death 1 Receptor