Single-cell analysis highlights the significance of malignant cell IFN/MHC-II for immunotherapy response in head and neck squamous cell carcinoma
Year: 2026
Type: article
Abstract: 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.
Source: Cell Reports Medicine
Authors: Michael Mints, Reilly A. Sample, Anuraag S. Parikh, Jesse M. Zaretsky, Zongtai Qi, Travis Law, Fudong Wang, Thomas F. Barrett, Riley Mullins, Ashley Reeb, Alissa C. Greenwald, Emily Stoller, Salma Ramadan, Sophie Gerndt, Peter Oppelt, Jessica Ley, Wade Thorstad, Randal C. Paniello, Jason T. Rich, Richard A. Harbison, Paul A. Zolkind, Ryan S. Jackson, Patrik Pipkorn, Douglas R. Adkins, Ravindra Uppaluri, Itay Tirosh, Sidharth V. Puram
Institutions: Karolinska Institutet, Weizmann Institute of Science, Washington University in St. Louis, Columbia University Irving Medical Center, Columbia University, University of Massachusetts Chan Medical School, Washington University Medical Center, Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W7147299909