Tumor immune microenvironment in oral cavity squamous cell carcinoma: Predictive Immunological Analysis with Imaging Mass Cytometry

• Applicant: Dr. Jakob Einhaus
• Subject Area: Dentistry, Oral Surgery ; Otolaryngology, Phoniatrics and Audiology ; Hematology, Oncology ; Pathology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501644547

• Final Report Year: 2025

Final Report Abstract

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity cancer and implies a poor prognosis (50% five-year mortality). Predictive biomarkers are critically needed to determine patients at risk for OTSCC recurrence to guide targeted development of novel treatment strategies. Complex interactions between tumor cells and adaptive and innate immune cells in the tumor immune microenvironment (TIME) contribute to OTSCC progression. From a cell function standpoint, the signaling state of innate immune cells (e.g., NF-κB, AKT, or JAK/STAT pathways) is an important driver for the formation of immunosuppressive cellular neighborhoods that contribute to tolerogenic adaptive cell responses as well as tumor proliferation, dedifferentiation, and immune evasion. Using a large-scale, two-center retrospective cohort study of primary OTSCC resection samples with associated clinical and outcomes data from 224 treatment-naïve patients, we investigated the spatial organization and functional activity of peri-tumoral immune cells that are critical for the pathobiology of OTSCC progression using imaging mass cytometry. In a first study, we analyzed samples from 48 patients to determine TIME features that correlate with OSCC tumor grade. We identified three immunological correlates of tumor differentiation that are associated with clinical outcomes (tumor recurrence and overall survival): granulocyte MAPKAPK2 signaling at the tumor front, stromal CD4+ memory T cell size, and the distance of fibroblasts from the tumor border. In a larger cohort of 198 patients and a 23.7% three-year recurrence rate, we are now aiming to identifying a predictive model for tumor recurrence after standard treatment. The entire dataset has over 9.8 million single cells from over 570 IMC images and is currently being analyzed. The results will provide a set of biomarkers prognostic for OTSCC recurrence to guide further studies to improve clinical management of patients with OTSCC and aid the development and monitoring of targeted immune-modifying therapies.

Publications

• High-multiplex tissue imaging in routine pathology—are we there yet?. Virchows Archiv, 482(5), 801-812.
  Einhaus, Jakob; Rochwarger, Alexander; Mattern, Sven; Gaudillière, Brice & Schürch, Christian M.
  
• Spatial subsetting enables integrative modeling of oral squamous cell carcinoma multiplex imaging data. iScience, 26(12), 108486.
  Einhaus, Jakob; Gaudilliere, Dyani K.; Hedou, Julien; Feyaerts, Dorien; Ozawa, Michael G.; Sato, Masaki; Ganio, Edward A.; Tsai, Amy S.; Stelzer, Ina A.; Bruckman, Karl C.; Amar, Jonas N.; Sabayev, Maximilian; Bonham, Thomas A.; Gillard, Joshua; Diop, Maïgane; Cambriel, Amelie; Mihalic, Zala N.; Valdez, Tulio; Liu, Stanley Y. ... & Han, Xiaoyuan
  
• Towards multiomic analysis of oral mucosal pathologies. Seminars in Immunopathology.
  Einhaus, Jakob; Han, Xiaoyuan; Feyaerts, Dorien; Sunwoo, John; Gaudilliere, Brice; Ahmad, Somayeh H.; Aghaeepour, Nima; Bruckman, Karl; Ojcius, David; Schürch, Christian M. & Gaudilliere, Dyani K.
  
• Discovery of sparse, reliable omic biomarkers with Stabl. Nature Biotechnology, 42(10), 1581-1593.
  Hédou, Julien; Marić, Ivana; Bellan, Grégoire; Einhaus, Jakob; Gaudillière, Dyani K.; Ladant, Francois-Xavier; Verdonk, Franck; Stelzer, Ina A.; Feyaerts, Dorien; Tsai, Amy S.; Ganio, Edward A.; Sabayev, Maximilian; Gillard, Joshua; Amar, Jonas; Cambriel, Amelie; Oskotsky, Tomiko T.; Roldan, Alennie; Golob, Jonathan L.; Sirota, Marina ... & Gaudillière, Brice