Defining the effects of bortezomib on NK cell activation in cancer

描述（由申请人提供）：癌症仍然是主要的死亡原因，少数民族社区的死亡人数不成比例。大多数常见的癌症对传统治疗是难治的。随着最近对癌症免疫监视机制的认识，我们的长期目标是阐明癌症消退的免疫机制，并开发可以特异性消除恶性细胞并为癌症患者提供持久益处的免疫治疗方法。最近在各种免疫排斥反应的病理生理学模型，包括癌症的研究表明，在适应性和先天性免疫效应细胞不可或缺的协同性。我们在肥大细胞瘤模型中的工作表明，CD8+ T细胞为休眠的自然杀伤（NK）细胞提供了必要的“帮助”，以激发其抗肿瘤功能。T细胞和NK细胞效应机制的这种协同性通过防止抗原缺陷型肿瘤逃逸变体的发展而导致完全的肿瘤消退。我们在小鼠肾细胞癌Renca的排斥反应中也观察到了CD8+ T细胞和NK细胞组合的类似作用，其他人在乳腺、膀胱和腹膜内间叶肿瘤的控制中也观察到了类似作用。这表明NK细胞和T细胞的功能协同性在肿瘤排斥反应中的重要性。然而，T细胞和NK细胞的这种保护性协同作用在侵袭性肿瘤固有的免疫抑制性慢性炎症条件下失败，如诱导型肿瘤模型所示。因此，有必要研究新的组合治疗策略及其机制的串扰，以减少肿瘤负荷和增强抗肿瘤免疫效应功能，通过推翻肿瘤诱导的免疫抑制。基于我们的初步数据，我们假设将肿瘤细胞死亡敏化硼替佐米给药与过继性NK细胞转移和免疫刺激性Notch激活相结合，应通过调节负性免疫调节回路来加强抗肿瘤免疫效应子功能。这种组合策略应该克服肿瘤微环境中慢性炎症的免疫抑制作用，并增强对癌症的治疗益处。为了验证我们的假设，我们提出解决以下具体目标：目标1：表征硼替佐米给药对肿瘤浸润淋巴细胞和骨髓细胞及其细胞因子和趋化因子在肿瘤微环境中产生的影响。目的2：评估硼替佐米对NK细胞效应器应答的影响。目的3：优化NK细胞过继治疗与硼替佐米和成簇多价DLL1治疗的组合在已建立的肿瘤中。该提议将是攻击在基于蛋白酶体抑制和免疫刺激性Notch信号传导的分子靶向背景下如何增强肿瘤特异性T细胞和NK细胞之间的抗肿瘤功能协同性的未充分探索的领域的第一次尝试。这些结果将为设计有效的免疫治疗方案提供新的见解，这些方案与大多数常规治疗难治的癌症相关，并将对癌症以外的病理生理条件产生影响。

DESCRIPTION (provided by applicant): Cancer remains the leading cause of death with a disproportionate toll on minority communities. Most common cancers are refractory to traditional treatments. With recent appreciation of cancer immunosurveillance mechanisms, our long-term objective is to elucidate immune mechanisms of cancer regression and to develop immunotherapy approaches that can specifically eliminate malignant cells and provide durable benefits in cancer patients. Recent studies in various pathophysiological models of immune rejection, including cancer, suggest an indispensable co-operativity in adaptive and innate immune effector cells. Our work in a mastocytoma model demonstrated that CD8+ T cells provided a necessary "help" to dormant natural killer (NK) cells in eliciting their antitumor function. This co-operativity of T cell and NK cell effector mechanisms led to complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. A similar role of combined CD8+ T cells and NK cells was also observed by us in the rejection of mouse renal cell carcinoma Renca and by others in the control of mammary, bladder and intraperitoneal mesenchymal tumors. This signifies the importance of functional co-operativity of NK cells and T cells in tumor rejection. However, this protective team-work of T cells and NK cells fails in conditions of immunosuppressive chronic inflammation intrinsic to aggressive tumors as shown in inducible tumor models. Thus, it is imperative to investigate novel combinatorial therapeutic strategies and their mechanistic cross-talk to reduce tumor burden and potentiate anti-tumor immune effector functions by overriding tumor-induced immunosuppression. Based on our preliminary data, we hypothesize that combining tumor cell-death sensitizing bortezomib administration with adoptive NK cell transfer and immunostimulatory Notch activation should strengthen anti-tumor immune effector functions by modulating negative immune-regulatory circuits. This combinatorial strategy should overcome immunosuppressive effects of the chronic inflammation in tumor microenvironment and enhance therapeutic benefits against cancer. To test our hypothesis, we propose to address the following specific aims: Aim 1: Characterize the impact of bortezomib administration on tumor-infiltrating lymphoid and myeloid cells and their cytokine and chemokine production in the tumor microenvironment. Aim 2: Assess the effects of bortezomib on NK cell effector responses. Aim 3: Optimize NK cell adoptive therapy in combination with bortezomib and clustered multivalent DLL1 treatments in an established tumor. This proposal will be the first attempt at attacking the underexplored area of how anti-tumor functional co-operativity between the tumor- specific T cells and NK cells can be enhanced in the context of molecular targeting based on proteasome inhibition and immunostimulatory Notch signaling. The results will provide new insights for designing effective immunotherapy protocols relevant to cancers refractory to most conventional treatments and will have implications for pathophysiological conditions beyond cancer.