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，肿瘤组织利用免疫检查点途径来削弱T细胞识别和消除异常癌细胞的能力。针对免疫检查点细胞毒性T淋巴细胞相关抗原4(CTLA4)的临床级抗体ipilimumab是提高晚期黑色素瘤患者总体生存率的第一种治疗方法。然而，尽管使用CTLA4阻断观察到显著而持久的缓解，但反应仍然局限于一小部分患者。此外，尽管增加ipilimumab的剂量可以显著改善整体肿瘤反应，但抗CTLA4单抗的治疗指数仍然受到免疫相关不良反应(IRAE)的发生的限制，如果不及时处理，这些不良反应可能危及生命。其他辐射会影响皮肤、肝脏和内分泌系统。因此，迫切需要开发新的策略，不仅增加抗肿瘤反应，而且将其从有害的免疫相关毒性中分离出来。尽管CTLA4被阻断，但免疫抑制的肿瘤微环境改变了T细胞效应器的功能，从而抑制了抗肿瘤反应。T细胞效应器功能在淋巴结(LN)中被激发，并在局部组织部位被包括树突状细胞(DC)和巨噬细胞(MPH)在内的抗原提呈细胞进一步调节。在过去的十年里，我们的团队一直专注于控制正常和肿瘤组织中DC和MPH的动态平衡和功能的机制。通过这一努力，我们发现了组织环境在调节DC和MPH功能中所起的指导作用。具体地说，我们发现细胞因子GM-CSF，最近被重新命名为CSF2，是由稳定状态肠道中的固有淋巴细胞产生的，以响应共生信号，促进DC和MPH产生维甲酸和IL-10，这是诱导肠道T调节细胞分化和扩张所必需的。这些结果扩展了德兰诺夫实验室之前的研究，表明CSF2驱动DC和MPH免疫调节。与此同时，我们和其他人发现，CSF2控制交叉呈递的皮肤CD103+DC的生存和功能，并在与TLR激动剂的局部组织递送相结合时促进疫苗CD8的细胞毒免疫。尽管一方面，利用产生CSF2的肿瘤细胞的疫苗策略已经导致了协调的抗肿瘤免疫反应，影响了患者的实质性肿瘤破坏，但这些成功已经被CSF2促进肿瘤免疫抑制效应的潜力所削弱。我们的新结果揭示了CSF2调节的免疫反应的作用机制，并揭示了CSF2的双重调节和免疫原性既依赖于产生CSF2的组织微环境，也取决于DC激活信号的可用性。我们的结果还表明，CSF_2的S在组织免疫中的区域化作用可以在临床上用于调节肿瘤患者的CTLA_4结局。基于这些结果，我们假设“通过利用CSF2对组织吞噬细胞功能的区隔作用，我们可以将抗肿瘤作用与免疫检查点阻断引起的有害免疫相关毒性分离”。