Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies
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<sup>+</sup> tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8<sup>+</sup> TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (T<sub>EM</sub>/T<sub>RM</sub>). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing T<sub>EM</sub>/T<sub>RM</sub> CD8<sup>+</sup> 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<sup>+</sup> T cells.
Authors
- Fei Tu (ORCID: https://orcid.org/0000-0001-5216-9850)
- Dario A.A. Vignali (ORCID: https://orcid.org/0000-0002-2771-5992)
- Lazar Vujanović (ORCID: https://orcid.org/0000-0003-1729-8619)
- Housaiyin Li
- Gabriel Sica
- Kevin J. Contrera (ORCID: https://orcid.org/0000-0002-2570-1706)
- Dan Paul Zandberg (ORCID: https://orcid.org/0000-0002-1002-8301)
- Mark Kubik (ORCID: https://orcid.org/0000-0002-8646-9920)
- Brian R. Isett (ORCID: https://orcid.org/0000-0002-1581-0706)
- Tullia C. Bruno (ORCID: https://orcid.org/0000-0002-6433-0207)
- Matthias Brand (ORCID: https://orcid.org/0000-0001-7194-7697)
- Umamaheswar Duvvuri (ORCID: https://orcid.org/0000-0003-1968-3756)
- Curtis M. Tatsuoka (ORCID: https://orcid.org/0000-0001-9991-4440)
- Shaum Sridharan (ORCID: https://orcid.org/0000-0001-6049-1508)
- Jing Hong Wang
- Simion I. Chiosea (ORCID: https://orcid.org/0000-0002-5766-8779)
- Aditi Kulkarni (ORCID: https://orcid.org/0000-0002-4886-6095)
- Robert L. Ferris (ORCID: https://orcid.org/0000-0001-6605-2071)
- Anthony R. Cillo (ORCID: https://orcid.org/0000-0002-3213-3129)
- Jie Chen (ORCID: https://orcid.org/0000-0002-2658-9525)
- Seungwon Kim (ORCID: https://orcid.org/0000-0003-1379-2601)
- Patricia M. Santos
- Marion Joy
- Riyue Bao
Institutions
- University of North Carolina Health Care (US)
- UPMC Hillman Cancer Center (US)
- University of Pittsburgh Medical Center (US)
- New York University (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1016/j.ccell.2025.02.026
- Citations
- 42
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 43.91
Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- University of Pittsburgh
- MacroGenics
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- EMD Serono
- Center for Research Computing, University of Pittsburgh
- National Cancer Institute