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Curative treatment of advanced, poorly immunogenic metastatic murine cancer models using an in situ vaccine, low-dose radiopharmaceutical, and immune checkpoint inhibition

ABSTRACT: Background Focal tumor radiation may prime adaptive anti-tumor immunity and this can be augmented by combination with intratumoral delivery of immune adjuvants. However, the abscopal propagation of anti-tumor immune response from such in situ vaccine (ISV) approaches is not consistently achieved in metastatic disease. Targeted radionuclide therapy (TRT) can deliver radiation to all tumor site in metastatic settings and low dose TRT can promote the clonal expansion and propagation of T cell-mediated anti-tumor immune response. We hypothesized that combining ISV to prime and low-dose TRT to propagate anti-tumor immunity could promote response to dual immune checkpoint blockade (DCP; anti-PD-L1 and anti-CTLA-4) in murine models of poorly immunogenic metastatic disease. Methods: C57BL/6 mice were engrafted with a primary tumor (right flank), a secondary tumor (left flank), and intravenously injected tumor cells to model advanced metastatic disease using the syngeneic MOC2 head and neck squamous cell carcinoma model or the B78 melanoma model. Mice were randomized to receive monotherapy or double or triple combinations of low-dose TRT, ISV targeting the primary tumor, and DCP. Tumor growth and survival were measured and mice rendered tumor-free mice were re-challenged with tumor engraftment to assess immune memory. Immune response was assessed by immunohistochemistry, flow cytometry, and quantitative PCR. Results: In two poorly immunogenic, syngeneic murine tumor models of advanced metastatic cancer, when compared to dual combinations or monotherapies, a triple combination of TRT+DCP+ISV enabled eradication of bulky well-established tumors, prevented development of lung metastases from circulating tumor cells (4 of 7 mice with circulating B16 melanoma and 14 of 15 mice with circulating MOC2 HNSCC developed no lung metastases), and extended survival (p < 0.01). This combination conferred T cell-dependent, tumor-specific immune memory, enabling uniform rejection of tumor re-engraftment (0% vs 100% for both B78 melanoma and MOC2 re-engraftment in disease-free triple-therapy treated mice vs age matched control mice). TRT+DCP+ISV activated both innate and adaptive immune response pathways in the primary and secondary tumors. Conclusions: Combining ISV and low-dose TRT is a promising approach to prime and propagate anti-tumor immunity and to promote response to checkpoint inhibition in settings of poorly immunogenic metastatic cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE304809 | GEO | 2026/07/02

REPOSITORIES: GEO

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Project description:We previously identified stress keratin 17 (K17) as a host factor that contributes to immune evasion in the context of mouse papillomavirus-induced disease. Analyses of head and neck squamous cell carcinoma (HNSCC) patient TCGA and tissue microarray data revealed that K17 can be overexpressed in both HPV+ and HPV- human cancer samples, with a more profound upregulation in HPV- HNSCC samples. In this report, we investigated the role of K17 in regulating immune response in HPV- head and neck cancer. To test whether K17 mediates immune evasion and resistance to immune checkpoint blockade (ICB) therapy in HPV- HNC, we used MOC2, a K17-expressing murine HNC cell line, and knocked out the K17 gene from it using CRISPR/Cas9 (K17KO MOC2 cells). Then we injected K17KO MOC2 cells or parental MOC2 cells into NSG and C57BL/6 mice and monitored tumor growth, immune cell infiltration, and response to ICB treatment in vivo. In NSG mice, the K17KO MOC2 cell lines grew as fast as parental MOC2 tumors. In C57BL/6 mice, K17KO MOC2 tumors grew significantly slower than parental MOC2 tumors, with 50% tumor rejection rate, in a T-cell dependent manner. Flow cytometry of tumor infiltrating T cells and bulk tumor RNA seq analyses show an active anti-tumor microenvironment in the K17KO MOC2 tumors, compared to parental MOC2 tumors. In addition, we observed that 5 out of 5 anti-PD1 + anti-CTLA4 treated K17KO MOC2 tumors completely regressed, while only 1 out of 5 parental MOC2 tumors similarly treated at the same size completely regressed (p<0.05). In exploring the role of chemokine CXCL9 in increased T cell infiltration, we blocked the receptor CXCR3, a receptor often upregulated on activated T cells, and saw a delay in the immune-mediated rejection K17KO MOC2 tumors. Single cell RNA seq analyses revealed a completely different immune landscape including both lymphoid and myeloid populations in K17KO MOC2 tumors. Overall, we demonstrated that K17 expression in HNSCC contributes to immune evasion and resistance to immune checkpoint blockade treatment through modulating the immune landscape in the tumor microenvironment.

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Curative treatment of advanced, poorly immunogenic metastatic murine cancer models using an in situ vaccine, low-dose radiopharmaceutical, and immune checkpoint inhibition

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