Lymphoma monocyte crosstalk: mechanisms of chemo-immunotherapy resistance

 描述(申请人提供)：伊琳博士，医学博士，现为梅奥诊所的临床血液学家。她的长期目标是在转译研究领域建立独立的学术生涯，以确定肿瘤介导的免疫抑制机制，开发克服这种抑制的策略，并在早期临床试验中测试这些策略。她的直接目标是为成功的R01应用程序生成数据，检查淋巴瘤相关单核细胞和肿瘤串扰促进淋巴瘤治疗耐药的机制。梅奥诊所拥有强大的癌症研究项目，并在培训成功的翻译和临床研究人员方面有着长期的记录。林博士得到了梅奥诊所癌症中心和爱荷华大学/梅奥诊所淋巴瘤孢子中心的支持，以确保能够获得足够的资源来完成拟议的项目。林博士的K22职业发展计划包括获得动物模型工作的能力，以及加强实际实验室经验，以建立一个独立资助的研究项目。在她目前的工作中，林博士发现，单核细胞在许多癌症类型中通常具有免疫抑制作用，并导致侵袭性疾病和不良的临床结果。她将淋巴瘤作为肿瘤模型，发现淋巴瘤相关单核细胞(LA-CD14)不仅具有免疫抑制作用，而且直接促进淋巴瘤对化疗的耐药性。在这项K22提案中，林博士将研究LA-CD14和淋巴瘤串扰促进治疗耐药的机制。这将通过两个特定的目的来实现：1)确定LA-CD14介导的促进淋巴瘤化疗耐药的机制。2)确定LA-CD14介导的抗肿瘤免疫保护淋巴瘤的机制。该项目的成功完成将为R01应用提供基础数据，以研究使淋巴瘤对化学免疫治疗重新敏感的具体策略。NCI K22奖项将为林博士从一名有指导的研究员转变为一名独立研究员提供关键支持。

 DESCRIPTION (provided by applicant): Dr. Yi Lin M.D. Ph.D. is currently a clinical hematologist at Mayo Clinic. Her long-term goal is to establish an independent academic career in translational research to identify mechanisms of tumor-mediated immune suppression, develop strategies to overcome this suppression, and test these strategies in early phase clinical trials. Her immediate goal is to generate data for a successful R01 application examining mechanisms of lymphoma-associated monocyte and tumor crosstalk that promote treatment resistance in lymphoma. Mayo Clinic has a strong cancer research program and a long track record of training successful translational and clinical researchers. Dr. Lin is supported by Mayo Clinic Cancer Center and the University of Iowa/Mayo Clinic Lymphoma SPORE to ensure adequate access to resources to complete the proposed project. Dr. Lin's K22 career development plan includes gaining competency in working with animal models and strengthening practical laboratory experience to establish an independently funded research program. In her current work, Dr. Lin has found that monocytes are commonly immune suppressive in many cancer types and contributes to aggressive disease and poor clinical outcome. Focusing on lymphoma as a tumor model, she has found that lymphoma-associated monocytes (LA-CD14) are not only immunosuppressive but also directly promote lymphoma resistance to chemotherapy. In this K22 proposal, Dr. Lin will examine mechanisms of LA-CD14 and lymphoma crosstalk that promote treatment resistance. This will be achieved through two specific aims: 1) Determine the mechanism of LA-CD14 mediated promotion of lymphoma resistance to chemotherapy. 2) Determine the mechanism of LA-CD14 mediated protection of lymphoma from anti-tumor immunity. Successful completion of this project will provide the foundational data for an R01 application to study specific strategies to re-sensitize lymphoma to chemo-immunotherapy. The NCI K22 award will provide critical support for Dr. Lin's transition from a mentored researcher to an independent investigator.