Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC

Robert Saddawi-Konefka (), Aoife O’Farrell, Farhoud Faraji, Lauren Clubb, Michael M. Allevato, Shawn M. Jensen, Bryan S. Yung, Zhiyong Wang, Victoria H. Wu, Nana-Ama Anang, Riyam Al Msari, Shiruyeh Schokrpur, Ida Franiak Pietryga, Alfredo A. Molinolo, Jill P. Mesirov, Aaron B. Simon, Bernard A. Fox, Jack D. Bui, Andrew Sharabi, Ezra E. W. Cohen, Joseph A. Califano and J. Silvio Gutkind ()
Additional contact information
Robert Saddawi-Konefka: Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine
Aoife O’Farrell: Moores Cancer Center, UC San Diego
Farhoud Faraji: Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine
Lauren Clubb: Moores Cancer Center, UC San Diego
Michael M. Allevato: Moores Cancer Center, UC San Diego
Shawn M. Jensen: Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center
Bryan S. Yung: Moores Cancer Center, UC San Diego
Zhiyong Wang: Moores Cancer Center, UC San Diego
Victoria H. Wu: Moores Cancer Center, UC San Diego
Nana-Ama Anang: Moores Cancer Center, UC San Diego
Riyam Al Msari: Moores Cancer Center, UC San Diego
Shiruyeh Schokrpur: Moores Cancer Center, UC San Diego
Ida Franiak Pietryga: Moores Cancer Center, UC San Diego
Alfredo A. Molinolo: Moores Cancer Center, UC San Diego
Jill P. Mesirov: Moores Cancer Center, UC San Diego
Aaron B. Simon: Moores Cancer Center, UC San Diego
Bernard A. Fox: Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center
Jack D. Bui: Moores Cancer Center, UC San Diego
Andrew Sharabi: Moores Cancer Center, UC San Diego
Ezra E. W. Cohen: Moores Cancer Center, UC San Diego
Joseph A. Califano: Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine
J. Silvio Gutkind: Moores Cancer Center, UC San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity.

Date: 2022
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DOI: 10.1038/s41467-022-31941-w

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