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，少数族裔社区的死亡人数不成比例。大多数常见的癌症对传统疗法是难以治愈的。随着对癌症免疫监测机制的最新认识，我们的长期目标是阐明癌症消退的免疫机制，并开发能够特异性地消除肿瘤细胞并为癌症患者提供持久益处的免疫治疗方法。最近对包括癌症在内的免疫排斥反应的各种病理生理学模型的研究表明，适应性免疫效应细胞和天然免疫效应细胞之间存在着不可或缺的协同作用。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)细胞在激发其抗肿瘤功能方面提供了必要的“帮助”。这种T细胞和NK细胞效应机制的协同作用，通过阻止抗原缺陷的肿瘤逃逸变异的发展，导致了肿瘤的完全消退。我们还观察到CD8+T细胞和NK细胞在小鼠肾细胞癌Renca的排斥反应中的作用，以及其他人在控制乳腺、膀胱和腹膜间充质肿瘤中的作用。这表明了NK细胞和T细胞在肿瘤排斥反应中功能协同作用的重要性。然而，这种T细胞和NK细胞的保护性团队工作在侵袭性肿瘤固有的免疫抑制慢性炎症条件下失败，如诱导性肿瘤模型所示。因此，迫切需要研究新的联合治疗策略及其机制串扰，以通过抑制肿瘤诱导的免疫抑制来减轻肿瘤负担并增强抗肿瘤免疫效应功能。根据我们的初步数据，我们推测，将肿瘤细胞死亡敏化的Bortezomib给药与过继的NK细胞转移和免疫刺激性Notch激活相结合，应该可以通过调节负免疫调节回路来增强抗肿瘤免疫效应功能。这一组合策略将克服肿瘤微环境中慢性炎症的免疫抑制效应，提高对癌症的治疗效果。为了验证我们的假设，我们建议解决以下具体目标：目标1：表征给药对肿瘤浸润性淋巴细胞和髓系细胞的影响，以及它们在肿瘤微环境中产生的细胞因子和趋化因子。目的2：评价硼替佐米对NK细胞效应的影响。目的3：在已建立的肿瘤中，优化NK细胞过继治疗联合Bortezomib和群集性多价DLL1治疗。这项提议将是第一次尝试攻击未被探索的领域，即如何在基于蛋白酶体抑制和免疫刺激Notch信号的分子靶向的背景下，增强肿瘤特异性T细胞和NK细胞之间的抗肿瘤功能合作。这一结果将为设计与大多数常规治疗难治的癌症相关的有效免疫治疗方案提供新的见解，并将对癌症以外的病理生理状况产生影响。

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.