Abstract Emerging evidence highlights the potential of lymphatic-sparing strategies in head and neck squamous cell carcinoma (HNSCC), as well as the sentinel lymph node (SLN) as a critical immunological niche1-3. Within this context, CCR7+ dendritic cells (DCs) have been identified as an essential subpopulation for the response to immunoradiotherapy4. Here, we investigated the therapeutic effect of intranodal CCR7 agonists CCL19/21 into the SLN using a sustained-release fibrin gel-conjugate system in the syngeneic, orthotopic, partially programmed death-1 inhibitor (PD-1i) sensitive 4MOSC1 model of HNSCC5, aiming to enhance DC function along the tumor-SLN axis. C57Bl/6 mice were injected with 4MOSC1 cells in the buccal space and underwent SLN mapping and injection of CCL19/21 conjugated (con.) to fibrinogen intranodal (i.n.), CCL19/21 unconjugated (uncon.) to fibrinogen i.n., PD-1i intraperitoneal (i.p.), CCL19/21 con. to fibrinogen i.n. + PD-1i i.p., or sham surgery following 6 days after tumor implantation. Animals were monitored for tumor volume and survival. Primary tumors were assayed by flow cytometry. Intranodal con. CCL19/21 led to a significantly reduced tumor growth (p= 0,0001 vs. sham) and complete response (CR) rate of 60%, whereas uncon. CCL19/21 i.n. (p=0,3354 vs. sham) and sham groups showed no CR. Combination of con. CCL19/21 + PD-1i significantly improved overall survival with 80% survival by day 34, compared to 60% for con. CCL19/21 i.n., and 0% for uncon. CCL19/21 i.n. and controls. Flow cytometric analysis 48 h following treatment shows enhanced DCs and enhanced activated DCs in tumors in con. CCL19/21 treated mice. Intranodal delivery of CCR7 agonists CCL19/21 significantly enhances DCs and activated DCs in tumors, reduces tumor growth and prolongs survival in the HNSCC 4MOSC1 mouse model. 1. Delclaux I et al. 2024;10(1):28-37.2. Saddawi-Konefka R et al. 2022;13(1):4298.3. Cochran AJ et al. 2006;6(9):659-670.4. Saddawi-Konefka R et al. 2025;16(1):6578.5. Wang Z et al. 2019;10(1):5546. Citation Format: Anais Aurelia Zourelidis, Jonathan Gunn, Tomoya Kurokawa, Sayuri Miyauchi, Kelsey Decker, Peter Vo, Pardis Mohammadzadeh, Jason Wu, Ester J. Kwon, Joseph A. Califano. Intranodal chemokine therapy targeting the sentinel lymph node in head and neck squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 448.
Zourelidis et al. (Fri,) studied this question.