Defining the effects of bortezomib on NK cell activation in cancer

描述（由申请人提供）：癌症仍然是导致死亡的主要原因，在少数民族社区造成的死亡人数不成比例。大多数常见的癌症对传统疗法是无效的。随着最近对癌症免疫监测机制的认识，我们的长期目标是阐明癌症消退的免疫机制，并开发能够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。最近对包括癌症在内的各种免疫排斥病理生理模型的研究表明，适应性和先天免疫效应细胞之间存在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细胞（NK）提供了必要的“帮助”，以激发其抗肿瘤功能。这种T细胞和NK细胞效应机制的协同作用，通过防止抗原缺陷肿瘤逃逸变异的发展，导致肿瘤完全消退。我们还观察到CD8+ T细胞和NK细胞的联合作用在小鼠肾细胞癌Renca的排斥反应中，以及在乳腺、膀胱和腹腔间充质肿瘤的控制中也有类似的作用。这表明NK细胞和T细胞在肿瘤排斥反应中的功能协同作用的重要性。然而，诱导肿瘤模型显示，在侵袭性肿瘤固有的免疫抑制性慢性炎症条件下，T细胞和NK细胞的这种保护性协同作用失效。因此，有必要研究新的组合治疗策略及其机制的相互作用，通过克服肿瘤诱导的免疫抑制来减轻肿瘤负担和增强抗肿瘤免疫效应功能。根据我们的初步数据，我们假设将肿瘤细胞死亡致敏硼替佐米与过继NK细胞转移和免疫刺激Notch激活相结合，可以通过调节负性免疫调节回路来增强抗肿瘤免疫效应功能。这种组合策略应克服肿瘤微环境中慢性炎症的免疫抑制作用，提高对癌症的治疗效果。为了验证我们的假设，我们提出解决以下具体目标：目的1：表征硼替佐米给药对肿瘤浸润淋巴细胞和髓细胞及其肿瘤微环境中细胞因子和趋化因子产生的影响。目的2：评估硼替佐米对NK细胞效应反应的影响。目的3：优化NK细胞过继治疗联合硼替佐米和聚集多价DLL1治疗已建立的肿瘤。这一建议将是首次尝试在基于蛋白酶体抑制和免疫刺激Notch信号的分子靶向背景下，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。该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性癌症相关，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.