Sunitinib Modulation of Cancer Immunotherapy

描述（由申请人提供）：受体酪氨酸激酶抑制剂（RTKI）舒尼替尼是转移性mCC （mRCC）的一线治疗药物，但所有患者最终都会对这种抗血管生成药物产生耐药性。与其他RTKIs不同，舒尼替尼还能阻止rcc诱导的髓源性抑制细胞（MDSC）的积累，并使1型T细胞功能正常化。我们观察到，无论舒尼替尼治疗期间肿瘤是否消退、稳定或进展，这种显著的免疫调节作用都发生在患者和动物身上。然而，在舒尼替尼发挥其作为免疫调节剂的全部治疗潜力之前，一些关键问题仍有待解决，包括肿瘤内MDSC抵抗舒尼替尼的能力，以及舒尼替尼抑制树突状细胞（DC）和MDSC积累的能力。拟议的研究将采用几种小鼠肿瘤模型以及来自IV期mRCC患者的血液和肿瘤样本来研究舒尼替尼对小鼠和癌症患者的免疫治疗影响。目的1将描述舒尼替尼阻止单核细胞- mdsc增殖、嗜中性细胞- mdsc分化和嗜中性细胞- mdsc存活的肿瘤增强机制。目的1还将探讨舒尼替尼阻断MDSC发展的这三个步骤的可能性，这是在每个步骤中混淆靶向不同rtk的结果。目的2将测试肿瘤和骨髓腔室中的MDSC对舒尼替尼表现出独特耐药性的机制，与外周腔室（如脾脏和血液）中MDSC对舒尼替尼的极端敏感性形成对比。我们暂时将这种舒尼替尼耐药性与局部暴露于GM-CSF和/或缺氧相关联，后者导致旁观者MDSC以stat3独立的方式发展，从而促进舒尼替尼耐药性和局部T细胞功能障碍。目的3将研究舒尼替尼抑制DC和MDSC积累的能力如何影响其在疫苗和过继T细胞免疫治疗中作为免疫调节剂的使用。我们将开发和测试免疫治疗策略，有效补偿舒尼替尼诱导的宿主DC耗竭，同时也旨在克服对舒尼替尼的室状MDSC耐药。这些研究应该提供必要的机制和技术见解，为未来的临床试验铺平明确的道路，以优化舒尼替尼在多种肿瘤类型的联合免疫治疗中的应用，包括那些可能对舒尼替尼治疗血管生成不敏感的肿瘤

DESCRIPTION (provided by applicant): The receptor tyrosine kinase inhibitor (RTKI) sunitinib is front-line therapy for metastatic mCC (mRCC), yet all patients eventually become resistant to this anti-angiogenic drug. Unlike other RTKIs, sunitinib also prevents RCC-induced accumulation of myeloid derived suppressor cells (MDSC) and normalizes type-1 T cell function. We observed that this remarkable immunomodulatory impact occurs both in patients and animals regardless of whether tumors regress, stabilize or progress during sunitinib therapy. Nevertheless, critical issues remain to be addressed before sunitinib can reach its full therapeutic potential as an immunomodulator, including the capacity of intratumoral MDSC to resist sunitinib, as well as sunitinib's capacity to inhibit dendritic cell (DC) in addition to MDSC accumulation.. The proposed studies will employ several murine tumor models as well as blood and tumor samples from stage IV mRCC patients to investigate sunitinib's immunotherapeutic impacts in both mouse and cancer patients. Aim 1 will delineate the mechanisms by which sunitinib prevents tumor enhancement of monocytic-MDSC proliferation, neutrophilic-MDSC differentiation, and neutrophilic-MDSC survival. Aim 1 will also explore the likelihood that sunitinib's blockade of these three steps of MDSC development is the consequence of promiscuous targeting of different RTKs at each step. Aim 2 will test the mechanism(s) by which MDSC in tumor and bone marrow compartments display distinctive resistance to sunitinib, contrasting to the extreme sunitinib susceptibility observed for MDSC in peripheral compartments such as spleen and blood.. We have tentatively correlated such sunitinib resistance to locally heightened exposure to GM-CSF and/or hypoxia which causes bystander MDSC to develop in a STAT3-independent manner, thus promoting sunitinib resistance and local T cell dysfunction. Aim 3 will investigate how sunitinib's capacity to inhibit DC as well as MDSC accumulation impacts its use as an immunomodulator in the setting of vaccine and adoptive T cell immunotherapy. We will develop and test immunotherapy strategies which effectively compensate for sunitinib-induced host DC depletion, and which also aim to overcome compartmental MDSC resistance to sunitinib. These studies should provide the necessary mechanistic and technical insights to pave a clear path for future clinical trials that optimize sunitinib's use in combination immunotherapy for multliple tumor types, including those which may not be angiogenically susceptible to sunitinib therapy