Single-cell analysis highlights the significance of malignant cell IFN/MHC-II for immunotherapy response in head and neck squamous cell carcinoma
In head and neck squamous cell carcinoma (HNSCC), immunotherapy response rates remain modest, with difficulty predicting responders. Previous studies characterizing immunotherapy-associated cellular changes in HNSCC focus on immune cells, providing limited insight into malignant cell responses. Here, we perform single-cell RNA sequencing (RNA-seq) on 16 HNSCC patients pre- and post-neoadjuvant pembrolizumab treatment. We identify an interferon (IFN)/major histocompatibility complex class II (MHC-II) expression program in malignant cells, characterized by MHC-II and IFN-response genes, which is associated with response to pembrolizumab. We validate malignant cell MHC-II expression at the protein level via multiplexed immunofluorescence. In a murine HNSCC model, IFN-γ-induced malignant cell MHC-II expression marks immunotherapy-sensitive tumors with favorable immune microenvironments. Finally, we confirm that pre-treatment malignant-IFN/MHC-II is a marker of response through deconvolution of bulk RNA-seq data from an independent cohort. Beyond identifying the malignant IFN/MHC-II program as a potential biomarker for immunotherapy response in HNSCC, our work elucidates the important role of malignant cells in immunotherapy.
Authors
- Travis Law (ORCID: https://orcid.org/0000-0002-7399-3299)
- Itay Tirosh (ORCID: https://orcid.org/0000-0001-5477-2987)
- Jessica Ley (ORCID: https://orcid.org/0000-0001-5092-8884)
- Fudong Wang (ORCID: https://orcid.org/0000-0003-2914-1360)
- Alissa Greenwald (ORCID: https://orcid.org/0000-0001-5428-9645)
- Ryan S. Jackson (ORCID: https://orcid.org/0000-0003-4626-2324)
- W. L. Thorstad
- Sidharth V. Puram (ORCID: https://orcid.org/0000-0003-3543-889X)
- Salma Ramadan (ORCID: https://orcid.org/0000-0003-4107-2337)
- R. Alex Harbison (ORCID: https://orcid.org/0000-0002-4695-6142)
- Patrik Pipkorn (ORCID: https://orcid.org/0000-0002-4118-7743)
- Ashley N. Reeb
- Michael Mints (ORCID: https://orcid.org/0000-0001-9215-9518)
- Riley Mullins (ORCID: https://orcid.org/0000-0002-7205-9971)
- Reilly A. Sample (ORCID: https://orcid.org/0000-0001-5830-5083)
- Anuraag S. Parikh (ORCID: https://orcid.org/0000-0003-0968-1028)
- Randal C. Paniello
- Thomas F. Barrett (ORCID: https://orcid.org/0000-0002-6058-1404)
- Jesse M. Zaretsky (ORCID: https://orcid.org/0000-0002-4889-2648)
- Sophie P. Gerndt (ORCID: https://orcid.org/0000-0001-9918-453X)
- Zongtai Qi (ORCID: https://orcid.org/0000-0002-0762-4209)
- Emily Stoller
- D. Adkins
- R. Uppaluri
- Jason T. Rich
- Peter Oppelt
- Paul A. Zolkind
Institutions
- University of Massachusetts Chan Medical School (US)
- Washington University in St. Louis (US)
- Columbia University Irving Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber Brigham Cancer Center (US)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1016/j.xcrm.2026.102715
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Doris Duke Charitable Foundation
- V Foundation for Cancer Research
- Cancer Research Foundation
- Foundation for Barnes-Jewish Hospital
- Israel Science Foundation
- National Cancer Institute
- National Institute of Dental and Craniofacial Research