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

描述（由申请人提供）：现在有明确的证据表明，肿瘤组织协同免疫检查点途径损害T细胞识别和消除异常癌细胞的能力。临床级抗体ipilimumab靶向免疫检查点细胞毒性t淋巴细胞相关抗原4 (CTLA4)，是第一种改善晚期黑色素瘤患者总生存率的治疗方法。然而，尽管通过CTLA4阻断观察到显著和持久的缓解，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）的限制，除非及时处理，否则可能危及生命。其他的辐射会影响皮肤、肝脏和内分泌系统。因此，迫切需要开发新的策略，不仅可以增加，而且还可以消除不必要的免疫相关毒性的抗肿瘤反应。尽管CTLA4被阻断，但抗肿瘤反应可能会因免疫抑制肿瘤微环境中T细胞效应功能的改变而减弱。T细胞效应功能在淋巴结（LN）中被激发，并在局部组织部位被抗原呈递细胞（包括树突状细胞（DC）和巨噬细胞（mph））进一步调节。在过去的十年中，我们的团队一直专注于控制DC和mph在正常和肿瘤组织中的稳态和功能的机制。通过这一努力，我们发现了组织环境在调节DC和mph功能中的指导作用。具体来说，我们发现细胞因子GM-CSF（最近更名为Csf2）是由稳态肠道先天淋巴细胞响应共生信号产生的，以促进DC和mph维甲酸和IL-10的产生，这是诱导肠道T调节细胞分化和扩增所必需的。这些结果扩展了Dranoff实验室先前的研究，表明Csf2驱动DC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，并在与TLR激动剂局部组织递送联合使用时促进疫苗CD8细胞毒性免疫。虽然一方面利用产生Csf2的肿瘤细胞的疫苗策略导致协调的抗肿瘤免疫反应，影响患者的实质性肿瘤破坏，但这些成功已经被Csf2促进肿瘤免疫抑制作用的潜力所缓和。我们的新结果揭示了Csf2调节免疫应答的作用机制，并揭示了Csf2的双重调节和免疫原性作用依赖于其产生的组织微环境和DC激活信号的可用性。我们的研究结果还表明，Csf2在组织免疫中的区隔作用可以在临床上用于调节癌症患者的CTLA4结果。基于这些结果，我们假设“通过利用Csf2对组织吞噬细胞功能的区隔作用，我们可以解开免疫检查点阻断诱导的有害免疫相关毒性的抗肿瘤作用”。

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".