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Updated: Sep 3, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor
Robert Saddawi-Konefka1,2,3, Aoife O'Farrell4,5, Farhoud Faraji6,4,7
1Department of Otolaryngology-Head and Neck Surgery, UC San Diego School of Medicine, San Diego, CA, USA. rsaddawi@health.ucsd.edu.
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.
Insights
Standard cancer treatments targeting lymphatics can block effective immune checkpoint inhibition (ICI). Preserving lymphatics is crucial for enhancing systemic antitumor immunity and improving patient outcomes in head and neck cancer.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibition (ICI) shows promise but has limited therapeutic responses.
- Standard cancer treatments may interfere with ICI efficacy.
Purpose of the Study:
- To investigate how regional lymphatics and associated immune cells influence ICI response in head and neck squamous cell carcinoma.
- To define lymphatic-preserving treatment strategies to enhance antitumor immunity.
Main Methods:
- Utilized murine models of head and neck squamous cell carcinoma with mapped tumor-draining lymphatics.
- Developed models for regional lymph node ablation via surgery or radiation.
- Analyzed immune cell populations and signaling pathways within tumor-draining lymphatics.
Main Results:
- Lymphatic ablation eliminated the ICI response, worsening survival and altering immune cell profiles.
- Tumor-draining lymphatics showed increased conventional type I dendritic cells and type I interferon signaling, essential for ICI response.
- These key immune components were lost following lymphablation.
Conclusions:
- Regional lymphatics are critical for mediating ICI efficacy in head and neck cancer.
- Standard therapies targeting lymphatics can impair antitumor immunity.
- Lymphatic-preserving strategies are needed to optimize ICI therapy and improve patient survival.
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