In situ radioimmunotherapy to maximize the engagement of conventional type 1 dendritic cells against non-T cell-inflamed tumors

原位放射免疫疗法可最大限度地发挥传统 1 型树突状细胞对抗非 T 细胞炎症肿瘤的作用

• 批准号: 10297983
• 负责人: Fumito Ito
• 金额: $ 41.02万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2021-12-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297983
• 关键词: Abscopal effect; Address; Affect; Agonist; Anti-CD40; Antigen Presentation; Antigens; Bilateral; Breast Melanoma; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Maturation; Cells; Cessation of life; Clinical; Contralateral; Data; Dendritic Cells; Development; Distant; Distant Metastasis; Event; FLT3 ligand; Foundations; Future; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Immunotherapy; In Situ; In complete remission; Investigation; Knowledge; Lesion; Ligands; Lung; Lymphoid; Malignant Neoplasms; Mediating; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Mus; Myelogenous; Myeloproliferative disease; Neoplasm Metastasis; Nonmetastatic; Outcome; PD-1/PD-L1; Patients; Phenotype; Poly I-C; Pre-Clinical Model; Primary Neoplasm; Property; Radiation; Radiation therapy; Radioimmunotherapy; Refractory; Regimen; Research; Resistance; Role; Sampling; Solid; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell inflamed; T-cell receptor repertoire; TLR3 gene; TNFRSF5 gene; Testing; Therapeutic; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Unresectable; Work; adaptive immune response; anti-PD-1/PD-L1; anti-PD-L1 antibodies; anti-PD-L1 therapy; base; cancer cell; cancer therapy; combinatorial; cytotoxic; draining lymph node; effective therapy; fetal liver kinase-2; immunogenic; immunogenicity; immunoregulation; improved; in vivo; insight; interest; malignant breast neoplasm; mouse model; neoplastic cell; novel; peripheral blood; radiation effect; response; stem; subcutaneous; targeted treatment; trafficking; tumor; tumor eradication; tumor microenvironment; tumor-immune system interactions

Radiation therapy (RT) is known to exert direct cytotoxic effects on tumor cells; however, recent research is revealing its influence on the immunogenicity of tumors, thus affecting the overall outcome of RT. While RT alone is usually insufficient to overcome the immunosuppressive tumor microenvironment (TME), strategies to boost immune-stimulating effects of RT are under intensive investigation. To date, most of the focus has been placed on immunomodulation after RT, in particular in combination with immune checkpoint inhibitors. Little is known about how manipulation of the TME before RT can impact on immunogenicity and therapeutic efficacy of RT. A growing body of evidence reveals that Batf3-dependent conventional type 1 dendritic cells (cDC1) rarely found within the tumor myeloid compartment have the important capacity of cross-presenting tumor-associated antigens (TAA) to CD8+ T cells, and act as `master regulators' for the T cell response in cancer. We hypothesize that in situ induction and activation of cDC1 enhances the therapeutic efficacy and immunogenicity of RT. To test this hypothesis, we developed a combinatorial in situ radioimmunotherapy comprised of in situ administration of: 1) Flt3L to mobilize cDC1 to the TME; 2) RT to promote immunogenic death of cancer cells and maturation of DC; and 3) dual TLR3/CD40 stimulation to activate antigen-loaded cDC1 for priming of tumor-specific CD8+ T cells. Our new data using multiple syngeneic orthotopic murine models of poorly immunogenic tumors insensitive to anti-PD-L1 therapy reveal that in situ radioimmunotherapy elicits de novo adaptive T cell responses that are characterized by novel clonotypes and stem-like Tcf1+ Slamf6+ phenotypes, renders tumors responsive to anti-PD-L1 antibody, mediates durable complete responses, and develops tumor-specific systemic immunological memory. Compelling evidence suggests that immunogenicity of RT can be enhanced by in situ induction and activation of cDC1; however, immunomodulatory effect of in situ radioimmunotherapy against distant metastatic tumors remains unclear. cDC1 prime CD4+ T cells as well as CD8+ T cells, but the role of CD4+ T cells in in situ radioimmunotherapy remains elusive. In addition, it remains unknown whether in situ radioimmunotherapy overcomes poor T-cell infiltration in human non-T cell-inflamed tumors. In this proposal we will elucidate the roles of CD4+ T cells in augmenting antitumor efficacy of in situ radioimmunotherapy (Aim 1). Additionally, we will seek to better understand the mechanisms underlying the immunomodulatory effect of in situ radioimmunotherapy targeting non-irradiated distant metastatic tumors (Aim 2). Finally, in Aim 3, we will seek to determine the alteration of the human TME in patients with unresectable and metastatic breast cancer treated with in situ radioimmunotherapy. These studies will add essential mechanistic understanding to how RT and the immune system interact, and provide insight into the clinical potential of in situ radioimmunotherapy against non-T cell-inflamed tumors insensitive to anti-PD-L1 therapy.

已知放射治疗（RT）对肿瘤细胞具有直接的细胞毒性作用；然而，最近的研究表明