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.

众所周知，放射治疗 (RT) 可对肿瘤细胞产生直接的细胞毒性作用；然而，最近的研究是 揭示其对肿瘤免疫原性的影响，从而影响 RT 的总体结果。当 RT 单独使用通常不足以克服免疫抑制肿瘤微环境（TME），策略 放疗增强免疫刺激作用的研究正在深入研究中。迄今为止，大部分关注点都集中在 放疗后进行免疫调节，特别是与免疫检查点抑制剂联合使用。小的是 了解 RT 之前 TME 的操作如何影响免疫原性和治疗效果 RT。越来越多的证据表明，依赖 Batf3 的传统 1 型树突状细胞 (cDC1) 很少 在肿瘤骨髓区室中发现的具有交叉呈递肿瘤相关细胞的重要能力 CD8+ T 细胞的抗原 (TAA)，并充当癌症 T 细胞反应的“主调节器”。我们假设 原位诱导和激活cDC1可增强RT的治疗效果和免疫原性。到 为了检验这一假设，我们开发了一种组合原位放射免疫疗法，包括原位给药 1) Flt3L 将 cDC1 动员至 TME； 2) 放疗促进癌细胞的免疫原性死亡和成熟 直流电； 3) TLR3/CD40双重刺激，激活负载抗原的cDC1，启动肿瘤特异性CD8+ T 细胞。我们的新数据使用了免疫原性差的肿瘤的多个同基因原位小鼠模型 对抗 PD-L1 疗法不敏感表明，原位放射免疫疗法可引发从头适应性 T 细胞反应 以新型克隆型和茎样 Tcf1+ Slamf6+ 表型为特征，使肿瘤产生反应 抗 PD-L1 抗体，介导持久的完全反应，并开发肿瘤特异性全身反应 免疫记忆。令人信服的证据表明，RT 的免疫原性可以通过原位增强 CDC1的诱导和激活；然而，原位放射免疫治疗的免疫调节作用 远处转移肿瘤仍不清楚。 cDC1 启动 CD4+ T 细胞以及 CD8+ T 细胞，但 CD4+ 的作用 原位放射免疫治疗中的 T 细胞仍然难以捉摸。此外，目前尚不清楚是否在原地 放射免疫疗法克服了人类非 T 细胞炎症肿瘤中 T 细胞浸润不良的问题。在这个提案中 我们将阐明 CD4+ T 细胞在增强原位放射免疫治疗的抗肿瘤功效中的作用（目标 1）。此外，我们将寻求更好地了解免疫调节作用的机制。 针对未照射的远处转移肿瘤的原位放射免疫治疗（目标 2）。最后，在目标 3 中，我们将 寻求确定不可切除和转移性乳腺癌患者的人类 TME 变化 采用原位放射免疫治疗。这些研究将为 RT 如何 和免疫系统相互作用，并深入了解原位放射免疫治疗的临床潜力 针对对抗 PD-L1 治疗不敏感的非 T 细胞炎症肿瘤。