4-1BB+ Tregs and inhibitory progenitor exhausted T cells confer resistance to anti-PD-L1 and anti-CTLA-4 combination therapy
Predictors of immune checkpoint inhibitor response in cancer remain elusive. From a previous phase 2 neoadjuvant immunotherapy window-of-opportunity study, we present the single-cell RNA and T cell receptor (TCR) sequencing analysis of 57 pre- and post-treatment tumor biopsies from head and neck cancer patients treated with durvalumab (anti-PD-L1) alone or with tremelimumab (anti-CTLA-4), identifying key cellular and molecular predictors of immune checkpoint inhibitor (ICI) response. Malignant cells and neutrophil senescence promote ICI response. While CXCL13<sup>+</sup> exhausted T (Tex) cells enhance response through 4-1BB signaling, anti-CTLA-4 induces 4-1BB<sup>+</sup> regulatory T cells (Tregs) restricting ICI efficacy. These opposing roles of 4-1BB in different cellular contexts may explain the limited benefit of combinatorial immunotherapy observed in clinical trials. We identify two subsets of tumor-reactive progenitor Tex (Tpex): ICI-responsive Tpex1 and ICI-resistant Tpex2, a subset characterized by KLRB1 and IL17R. The balance of Tpex1 and Tpex2 associates with ICI response across multiple cancers, offering insights into sustaining response. This study was registered at ClinicalTrials.gov (NCT03737968).
Authors
- Nam Suk Sim (ORCID: https://orcid.org/0000-0002-5567-8076)
- Dahee Kim (ORCID: https://orcid.org/0000-0001-7286-1334)
- Min Hee Hong (ORCID: https://orcid.org/0000-0003-3490-2195)
- Sun Och Yoon (ORCID: https://orcid.org/0000-0002-5115-1402)
- Seungbyn Baek (ORCID: https://orcid.org/0000-0002-4039-277X)
- Junha Cha (ORCID: https://orcid.org/0000-0002-3106-5865)
- Insuk Lee (ORCID: https://orcid.org/0000-0003-3146-6180)
- Hyun O. Lee (ORCID: https://orcid.org/0000-0003-0102-4795)
- Youngmi Jung (ORCID: https://orcid.org/0000-0003-2189-0658)
- Hyun Jun Hong (ORCID: https://orcid.org/0000-0002-7808-7877)
- Chang Gon Kim (ORCID: https://orcid.org/0000-0002-4929-8501)
- Jinna Kim (ORCID: https://orcid.org/0000-0002-9978-4356)
- Gamin Kim (ORCID: https://orcid.org/0000-0001-8504-7921)
- Eun Young Seong (ORCID: https://orcid.org/0000-0002-6006-0051)
- Yoon Woo Koh (ORCID: https://orcid.org/0000-0002-9734-1682)
- Seokhyeong Go
- Jeong‐Ah Kim (ORCID: https://orcid.org/0000-0003-4949-4913)
- Wonrak Son
- Jaehyung Kim (ORCID: https://orcid.org/0000-0003-2568-9951)
- Kyung Hwan Kim
Institutions
- Pohang University of Science and Technology (KR)
- Yonsei University (KR)
- Severance Hospital (KR)
- Yonsei University Health System (KR)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-10-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102408
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- AstraZeneca
- National Research Foundation
- Yonsei University
- Ministry of Trade, Industry and Energy
- Korean Foundation for Cancer Research
- Ministry of Science and ICT, South Korea
- Yonsei University College of Medicine