Harnessing Csf-2 compartmentalized role on tissue resident phagocytes to uncouple anti-tumoral from pathological immunity induced by checkpoint inhibitors

利用 Csf-2 对组织驻留吞噬细胞的区室化作用，将抗肿瘤作用与检查点抑制剂诱导的病理免疫作用分开

• 批准号: 9228983
• 负责人: MIRIAM MERAD
• 金额: $ 38.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-06 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228983
• 关键词: Address; Adjuvant; Adverse effects; Adverse event; Affect; Agonist; Antibodies; Antigen-Presenting Cells; Antitumor Response; CD8B1 gene; Cancer Patient; Cell Differentiation process; Cells; Clinical; Cutaneous; Cytotoxic T-Lymphocyte-Associated Protein 4; Dendritic Cells; Disease remission; Dose; Eastern Cooperative Oncology Group; Effector Cell; Endocrine system; Enterocolitis; Environment; Gastrointestinal tract structure; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Impairment; Incidence; Injury; Instruction; Interleukin-10; Intestines; Laboratories; Life; Light; Liver; Lung; Lymphocyte; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mediating; Metastatic Melanoma; Molecular; Mononuclear; Mucous Membrane; Normal tissue morphology; Outcome; Pathologic; Pathway interactions; Patients; Peripheral; Phagocytes; Physiological; Play; Production; Randomized; Regulatory T-Lymphocyte; Role; Science; Signal Transduction; Site; Skin; Solid Neoplasm; Symbiosis; T-Lymphocyte; TLR3 gene; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Tretinoin; Tumor Immunity; Tumor Tissue; Unresectable; Vaccines; advanced disease; antitumor effect; arm; base; cancer cell; cytokine; cytotoxic; immune checkpoint; immune checkpoint blockade; immunogenic; immunoregulation; improved; lung small cell carcinoma; lymph nodes; macrophage; malignant stomach neoplasm; melanoma; neoplastic cell; novel strategies; patient subsets; phase II trial; prevent; public health relevance; response; success; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): There is now clear evidence that tumor tissues co-opt immune-checkpoint pathways to impair T cell ability to recognize and eliminate abnormal cancer cells. The clinical grade antibody, ipilimumab targeting the immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) was the first therapy to improve overall survival in patients with advanced melanoma. However, despite significant and long lasting remissions observed with CTLA4 blockade, responses remain limited to a subset of patients. In addition, although increasing doses of ipilimumab can significantly improve overall tumor responses, the therapeutic index of anti-CTLA4 mAb remains limited by the occurrence of immune-related adverse effects (irAE) that can be life threatening, unless promptly managed. Other irAE affect the skin, liver and the endocrine system. There is therefore an urgent need to develop novel strategies to not only increase, but to also uncouple, anti-tumor responses from unwanted immune related toxicities. Antitumor responses may be curtailed by alteration of T cell effector functions by an immunosuppressive tumor microenvironment despite the of CTLA4 blockade. T cell effector function is elicited in the lymph nodes (LN) and further modulated at local tissue sites by antigen presenting cells that include dendritic cells (DC) and macrophages (mph). Over the past decade, our group has been focusing on the mechanisms that control the homeostasis and function of DC and mph in normal and tumor tissues. Through this effort we discovered the instructive role played by the tissue environment in modulating DC and mph function. Specifically, we discovered that the cytokine GM-CSF, recently renamed Csf2, was produced by innate lymphocyte cells in the steady state gut in response to commensal signals to promote DC and mph production of retinoic acid and IL-10 that are necessary to induce intestinal T regulatory cell differentiation and expansion. These results extend previous studies by the Dranoff's laboratory showing that Csf2 drive DC and mph immunoregulation. Concomitantly, we and others have found that Csf2 controls the survival and function of cross-presenting cutaneous CD103+ DC and promotes vaccine CD8 cytotoxic immunity when combined with local tissue delivery of TLR agonists. Though on the one hand vaccine strategies utilizing Csf2-producing tumor cells have led to coordinated antitumor immune responses affecting substantial tumor destruction in patients, these successes has been tempered by the potential of Csf2 to promote tumor immunosuppressive effects. Our new results shed a new light into the mechanisms of action of Csf2-regulated immune responses and reveal that the dual regulatory and immunogenic role of Csf2 is dependent on both the tissue microenvironment in which it is produced and on the availability of DC activating signals. Our results also suggest that Csf2's compartmentalized role in tissue immunity could be exploited clinically to modulate CTLA4 outcome in cancer patients. Based on these results we hypothesize that "By harnessing Csf2 compartmentalized role on tissue phagocyte function we could uncouple anti-tumoral effects from unwanted immune related toxicity induced by immune checkpoint blockade".

描述（由申请人提供）：现在有明确的证据表明，肿瘤组织同时进行了免疫检查途径，以损害T细胞识别和消除异常癌细胞的T细胞能力。临床级抗体，靶向免疫检查点细胞毒性T淋巴细胞相关的抗原4（CTLA4）的ipilimumab是提高晚期黑色素瘤患者总体生存率的第一种疗法。然而，尽管CTLA4封锁观察到了明显且持久的恢复，但反应仍然仅限于一部分患者。此外，尽管增加剂量的ipilimumab可以显着改善整体肿瘤反应，但抗CTLA4 MAB的治疗指数仍受到免疫相关的不良反应（IRAE）的限制，除非迅速管理，否则可能会危及生命。其他IRAE会影响皮肤，肝脏和内分泌系统。因此，迫切需要制定新的策略，不仅增加，而且还要与不需要的免疫相关毒性产生的抗肿瘤反应。 尽管CTLA4阻滞剂会通过免疫抑制性肿瘤微环境改变T细胞效应子功能，可以减少抗肿瘤反应。 T细胞效应的功能在淋巴结（LN）中引起，并通过包括树突状细胞（DC）和巨噬细胞（MPH）的抗原呈递细胞在局部组织部位进行了进一步调节。在过去的十年中，我们的小组一直集中在控制正常和肿瘤组织中DC和MPH的稳态和功能的机制上。通过这项努力，我们发现了组织环境在调节直流和MPH功能中起的启发性作用。具体而言，我们发现，最近更名为CSF2的细胞因子GM-CSF是由稳态肠道中的先天淋巴细胞细胞生成的，响应于共生信号，以促进视黄酸和MPH的产生，这些dc和MPH的产生是诱导无肠T调节性细胞分化和扩张所必需的。这些结果扩大了德拉诺夫实验室先前的研究，表明CSF2驱动直流和MPH免疫调节。同时，我们和其他人发现，CSF2控制交叉呈递皮肤CD103+ DC的存活和功能，并促进疫苗CD8 CD8细胞毒性免疫，与TLR激动剂的局部组织递送结合使用。尽管一方面利用CSF2产生的肿瘤细胞的疫苗策略导致了影响患者实质性肿瘤破坏的协调抗肿瘤免疫反应，但CSF2的潜力促进了这些成功，促进肿瘤免疫抑制作用。我们的新结果对CSF2调节的免疫反应的作用机理有了新的启示，并揭示了CSF2的双重调节和免疫原性作用取决于其产生的组织微环境以及DC激活信号的可用性。我们的结果还表明，可以在临床上利用CSF2在组织免疫中的分室作用，以调节癌症患者的CTLA4结果。基于这些结果，我们假设“通过利用CSF2在组织吞噬细胞功能上的CSF2分室作用，我们可以将抗肿瘤效应与免疫检查点阻断引起的不良免疫相关毒性取消抗肿瘤效应”。