{
  "abstract": "Background Immune-suppressive tumor microenvironments (TME) have limited the impact of immune checkpoint blockade (ICB) and cellular immunotherapies in solid tumors, often by restricting the infiltration and activation of anti-tumoral T and NK cells. The chemokine receptor CXCR3 is a key regulator of cytotoxic immune function, responding to IFN-inducible ligands CXCL9, CXCL10, and CXCL11 to control the migration and spatial distribution of activated T and NK cells. CXCL9 and 10 are important for the anti-tumoral functions of CD8 + T cells, type-1 helper (Th1) CD4+ T cells, and NK cells and reduced expression of either ligand contributes to immune exclusion within the TME.1–3 Conversely, the elevated expression of CXCL9, CXCL10 and CXCR3 has been associated with improved responses to ICB treatment.4 Methods These findings indicate that, by boosting tumor-localized CXCL10 levels through intratumoral (IT) delivery of recombinant ligand, it may be possible to override immunosuppressive mechanisms and reprogram the TME a state more responsive to immunotherapies. To explore this, we leverage the 4NQO-induced Murine Oral Squamous Cell (4MOSC1) carcinoma and Murine Oral Carcinoma (MOC1) mouse models of HNSCC.Results We demonstrated that intratumoral augmentation of CXCL10 increases the infiltration of cytotoxic effector cells (CD8+ T cells, CD4+ T cells, and NK cells), leading to suppressed tumor growth and recurrence. 5 Our data also suggests that IT-CXCL10 also drives tumor clearance by promoting the effector function of T cells, with recruited T cells displaying increased tumor antigen specificity, penetrance into the tumor parenchyma, and enhanced cytotoxic effector function, such as granzyme release. Additionally, despite administration of CXCL10 into tumors, CD8+ T and CD4+ T cells show increased proliferation in tumor-draining lymph nodes (TdLNs), consistent with enhanced priming and trafficking of antigen presenting cells (APCs) between tumors and TdLNs. Therefore, IT-CXCL10 suppresses tumor growth and recurrence by directly and indirectly mobilizing a network of immune cells that support a multimodal program of anti-tumoral activities, extending beyond the TME.5 Combining IT-CXCL10 and anti-PD-1 further increased tumor clearance in our models. As our IT method limits chemokine activity to the tumor, we aim to determine if CXCL10/ICB combination treatments reduce the risk of immune-related adverse events (irAEs) by enabling anti-tumor efficacy to be achieved with lower doses of systemic ICB treatment.Conclusions Overall, these findings provide the rationale for clinical evaluation of chemokine-based therapeutics, like IT-CXCL10, as strategies to modulate the immune composition of the TME to enhance sensitivity to ICB and cellular immunotherapies.Acknowledgements We would like to acknowledge Elsa Molina (Salk OMICS core) for the preparation of samples with the nCounter platform and data analysis training as well as Cheryl Kim (LJI Flow Cytometry Core) and Michael Rose and Valeria Estrada (BTTSR Core, UC San Diego). We would also like to thank John Chang and Jack Bui (UC San Diego) for helpful discussions. All cartoon renderings were created using https://www.biorender.com. Funding: This project was supported by grants from the National Institute of Dental and Craniofacial Research (NIH/NIDCR R01DE033909-01) and the Moores Cancer Center, Delivering Discoveries: Jawsome Shark Tank Multidisciplinary Pilot Project Program (NIH 2P30CA023100) (both to TMH and JSG). CKS was supported by the Pharmacological Sciences Pre-Doctoral Training Program (5T32GM007752-40), the Tribal Member Initiative (TMI) Pre-doctoral Fellowship, and the Cancer Cell Signaling and Communication Post-doctoral Training Grant (NIH/NCI T32 CA009523). RSK was supported by the NRSA Training Award (NIH/NIDCR F32DE029990-01). Competing interests: TMH is a cofounder of Lassogen Inc. and serves on the Scientific Advisory Boards of Abilita Bio, Abalone Bio and Aikium Inc. JSG reports consulting fees from Radionetics Oncology, BTB Therapeutics, Pangea Therapeutics, and io9 and is the founder of Kadima Pharmaceuticals. SS receives consulting fees from OncoHost and Navya. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.References Mikucki M, Fisher D, Matsuzaki J, Skitzki J, Gaulin N, Muhitch J, Ku A, Frelinger J, Odunsi K, Gajewski T, Luster A, Evans S. Non-redundant requirement for CXCR3 signaling during tumoricidal T cell trafficking across tumor vascular checkpoints. Nat Commun. 2015;6:7458.Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE, Freeman GJ, Boland GM, Luster AD. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti- PD-1 therapy. Immunity. 2019;50:1498–1512.e5.Wendel M, Galani IE, Suri-Payer E, Cerwenka A. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res. 2008;68:8437–8445.House IG, Savas P, Lai J, Chen AXY, Oliver AJ, Teo ZL, Todd KL, Henderson MA, Giuffrida L, Petley EV, Sek K, Mardiana S, Gide TN, Quek C, Scolyer RA, Long GV, Wilmott JS, Loi S, Darcy PK, Beavis PA. Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clinical Cancer Research 2020;26:487–504.Shinn CK, Saddawi-Konefka R, Salanga CL, Schokrpur S, Gutkind JS, Handel TM. Activating the CXCR3/CXCL10 pathway overrides tumor immune suppression by enhancing immune trafficking and effector cell priming in head and neck squamous cell carcinoma. bioRxiv. Preprint. 2025. bioRxiv:2025.04.24.650529.",
  "authors": [
    {
      "affiliations": [
        "UC San Diego Health, La Jolla, CA, USA",
        "Moores Cancer Center, La Jolla, CA, USA"
      ],
      "name": "Cheyanne K Shinn"
    },
    {
      "affiliations": [
        "MD Anderson, La Jolla, CA, USA"
      ],
      "name": "Robert Saddawi-Konefka"
    },
    {
      "affiliations": [
        "UC Davis, Sacramento, CA, USA"
      ],
      "name": "Shiruyeh Schokrpur"
    },
    {
      "affiliations": [
        "UC San Diego Health, La Jolla, CA, USA"
      ],
      "name": "Catherina Salanga"
    },
    {
      "affiliations": [
        "UC San Diego Health, La Jolla, CA, USA",
        "Moores Cancer Center, La Jolla, CA, USA"
      ],
      "name": "J Silvio Gutkind"
    },
    {
      "affiliations": [
        "UC San Diego Health, La Jolla, CA, USA"
      ],
      "name": "Tracy M Handel"
    }
  ],
  "title": "871 Immune architecture by design: chemokines as tools to sculpt the immune composition of solid tumors",
  "uid": "723f3a3b-e99b-59e9-b11e-713d0f400f52"
}