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: 10600657
• 负责人: Fumito Ito
• 金额: $ 40.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600657
• 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 gene; 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; 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; 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.

已知辐射疗法（RT）对肿瘤细胞产生直接的细胞毒性作用。但是，最近的研究是 揭示其对肿瘤免疫原性的影响，从而影响RT的整体结果。而RT 通常，单独的不足以克服免疫抑制肿瘤微环境（TME），策略 RT的增强免疫刺激作用正在进行深入研究。迄今为止，大多数重点是 在RT后进行免疫调节，特别是与免疫检查点抑制剂结合使用。几乎没有 知道在RT之前对TME的操纵如何影响免疫原性和治疗功效 RT。越来越多的证据表明，BATF3依赖性常规1个树突状细胞（CDC1）很少 在肿瘤髓样室内发现的具有交叉肿瘤相关的重要能力 对CD8+ T细胞的抗原（TAA），充当癌症中T细胞反应的“主调节剂”。我们假设 CDC1的原位诱导和激活增强了RT的治疗功效和免疫原性。到 检验该假设，我们开发了一个由原位给药组成的原位原位放射免疫疗法 的：1）FLT3L将CDC1动员到TME； 2）RT促进癌细胞的免疫原性和成熟 DC; 3）双重TLR3/CD40刺激激活抗原加载的CDC1，以启动肿瘤特异性CD8+ T 细胞。我们的新数据使用多种合成性的原位鼠模型的免疫原性肿瘤模型 对抗PD-L1疗法不敏感的表明，原位放射免疫疗法引起了自适应T细胞反应 以新颖的clonotypes和类似茎状的TCF1+ SLAMF6+表型为特征，使肿瘤反应灵敏 抗PD-L1抗体，介导耐用的完整反应并发展肿瘤特异性的全身性 免疫记忆。令人信服的证据表明，RT可以通过原位增强RT的免疫原性 CDC1的诱导和激活；然而，原位放射免疫疗法的免疫调节作用 远处的转移性肿瘤尚不清楚。 CDC1 Prime CD4+ T细胞以及CD8+ T细胞，但CD4+的作用 原位放射免疫疗法的T细胞仍然难以捉摸。此外，是否原位仍然未知 放射免疫疗法克服了人类非T细胞增添肿瘤的T细胞浸润较差。在此提案中 我们将阐明CD4+ T细胞在增强原位放射免疫疗法的抗肿瘤功效中的作用（AIM 1）。此外，我们将寻求更好地了解免疫调节作用的基础机制 原位放射免疫疗法靶向非辐照远处转移性肿瘤（AIM 2）。最后，在AIM 3中，我们将 寻求确定无法切除和转移性乳腺癌患者的人类TME改变 接受原位放射免疫疗法治疗。这些研究将为RT增添基本的机械理解 免疫系统相互作用，并深入了解原位放射性疗法的临床潜力 针对对抗PD-L1治疗不敏感的非T细胞增添肿瘤。