MHC class I upregulation contributes to the therapeutic response to radiotherapy in combination with anti-PD-L1/anti-TGF-β in squamous cell carcinomas with enhanced CD8 T cell memory-driven response

Hanne T Lind; Spencer C Hall; Alexander A Strait; Jack B Goon; John D Aleman; Samantha M Y Chen; Sana D Karam; Christian D Young; Jing H Wang; Xiao-Jing Wang

doi:10.1016/j.canlet.2024.217347

MHC class I upregulation contributes to the therapeutic response to radiotherapy in combination with anti-PD-L1/anti-TGF-β in squamous cell carcinomas with enhanced CD8 T cell memory-driven response

Cancer Lett. 2024 Nov 21:217347. doi: 10.1016/j.canlet.2024.217347. Online ahead of print.

Authors

Affiliations

¹ Department of Pathology, University of California, Davis, CA.
² Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO.
³ Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO.
⁴ UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, Department of Immunology, University of Pittsburg, Pittsburgh, PA.
⁵ Department of Pathology, University of California, Davis, CA; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO; VA Northern California Health Care System, Sacramento, CA. Electronic address: drxwang@ucdavis.edu.

PMID: 39580046
DOI: 10.1016/j.canlet.2024.217347

Abstract

Radiation therapy (RT), a mainstay treatment for head and neck squamous cell carcinoma (HNSCC), kills cancer cells and modulates the tumor immune microenvironment. We sought to assess the effect of RT in combination with PD-L1/TGF-β dual blockade in squamous cell carcinomas (SCC) and analyze the underlying mechanisms. We transplanted mouse SCC cells derived from keratin-15 (K15) stem cells harboring Kras^G12D/Smad4^-/- mutations into syngeneic recipients and irradiated tumors followed by PD-L1/TGF-β dual blockade. We identified a responder line and a non-responder line to this combination therapy. Responder hosts eradicated SCCs by the combined therapy and rejected re-transplanted SCC cells 6 months post tumor eradication, which correlated with clonotype expansions of splenic CD8 T cells and effector memory gene expression identified by single cell sequencing of TCR and transcriptomes, respectively. Mechanistically, RT upregulated MHC-I (major histocompatibility complex I) and its transcriptional regulators including NLRC5, in SCCs of the responders but not non-responders. These data are consistent with the TCGA HNSCC database in which NLRC5 correlated to MHC-I genes and CD8 T cell gene expression. Functional contribution of MHC-I to PD-L1/TGF-β blockade response was confirmed by knocking out beta-2-microglobulin in responder cells that attenuated the response to the same therapy. Thus, the therapeutic effectiveness appeared to largely depend on cancer-cell MHC-I expression, triggering CD8 T cell effector memory-driven responses against tumor cell antigens. Identifying the differential RT response to MHC-I induction may serve as a predictive marker for stratifying patients that are most likely to benefit from this combination therapy.

Keywords: MHC class I; PD-L1; Squamous cell carcinoma; T cell; TGF-β; immunotherapy; radiotherapy.