Tissue Resident memory T cell responses to cancer

组织驻留记忆（TRM）细胞是免疫系统中针对感染性病原体的有效介质。 外周组织我们实验室发表的研究现在确立了TRM细胞在免疫中的关键作用 到癌症我们发现，免疫疗法诱导的CD 8 TRM细胞介导对皮肤黑色素瘤的免疫， 自身免疫性白癜风是产生这些持久保护性TRM细胞的关键宿主要求。白癜风 长期以来被认为是黑色素瘤患者的积极预后因素。我们发现白癜风的皮肤- 受影响的小鼠为记忆T细胞的驻留提供了一个适宜的小生境，记忆T细胞提供了持久的，保护性的， 抗肿瘤免疫我们假设外周血中功能性记忆T细胞的多样性补充， 在小鼠和白癜风及其他黑色素瘤患者中观察到， 皮肤炎症事件。我们的第一个具体目标将是确定TRM细胞的贡献， 转移性肿瘤保护。白癜风小鼠也保持对肺转移的保护，我们的研究表明， 初步数据揭示了白癜风小鼠肺中肿瘤特异性TRM细胞的独特群体。我们将 检验肺TRM细胞和淋巴TEM细胞一起防止转移性黑素瘤生长的假设， 并定义肺和皮肤TRM细胞的核心转录标记。我们的第二个具体目标是定义 皮肤中保护性TRM回忆反应的肿瘤抗原特异性。我们的数据显示白癜风中的TRM细胞- 受影响的皮肤对黑素细胞/黑色素瘤共有抗原具有特异性， 抗原的我们将确定抗原识别如何影响T细胞功能和TRM小生境的竞争， 并检验对肿瘤/自身抗原和新抗原都具有特异性的TRM细胞介导肿瘤/自身抗原和新抗原表达的假设。 排斥皮肤中的黑色素瘤和非黑色素瘤肿瘤。最后，我们的第三个具体目标将是确定 抗原无关的皮肤炎症在促进TRM对黑色素瘤反应中的作用。我们将测试 假设黑素细胞无关的皮肤炎症可以产生黑色素瘤特异性TRM细胞， 评估患有白癜风和其他皮肤病的黑色素瘤患者皮肤活检中的TRM细胞反应 炎症事件。临床前工作将集中在促进TRM反应的治疗方法上， 与免疫检查点抑制结合。总的来说，这个项目将定义驻留内存T的作用 细胞对癌症的免疫反应。通过证明TRM细胞在整个宿主中的基本作用， 这些研究预计将对癌症免疫的方式产生变革性影响， 免疫疗法被递送和评估。

Tissue-resident memory (TRM) cells are potent mediators of immunity against infectious pathogens in peripheral tissues. Published studies from our laboratory now establish a crucial role for TRM cells in immunity to cancer. We show that immunotherapy-induced CD8 TRM cells mediate immunity to melanoma in the skin, and that autoimmune vitiligo is a key host requirement for generating these durably protective TRM cells. Vitiligo has long been recognized as a positive prognostic factor in melanoma patients. We find that the skin of vitiligo- affected mice provides a hospitable niche for the residence of memory T cells that provide durable, protective, antitumor immunity. We hypothesize that a diverse complement of functional memory T cells in peripheral tissues underlies the durable tumor immunity observed in mice and melanoma patients with vitiligo and other cutaneous inflammatory events. Our first Specific Aim will be to determine the contribution of TRM cells to metastatic tumor protection. Mice with vitiligo also maintain protection against lung metastases, and our preliminary data reveal a distinct population of tumor-specific TRM cells in the lungs of mice with vitiligo. We will test the hypothesis that lung TRM cells and lymphoid TEM cells together prevent metastatic melanoma growth, and define a core transcriptional signature for lung and skin TRM cells. Our second Specific Aim will be to define the tumor antigen specificity of protective TRM recall responses in skin. Our data show that TRM cells in vitiligo- affected skin have specificity for melanocyte/melanoma shared antigens, as well as a model tumor-specific antigen. We will determine how antigen recognition affects T cell function and competition for the TRM niche, and test the hypothesis that TRM cells with specificity for both tumor/self antigens and neoantigens mediate the rejection of melanoma and non-melanoma tumors in the skin. Finally, our third Specific Aim will be to determine the role of antigen-unrelated cutaneous inflammation in promoting TRM responses to melanoma. We will test the hypothesis that melanocyte-unrelated skin inflammation can generate melanoma-specific TRM cells by assessing TRM cell responses in skin biopsies from melanoma patients with vitiligo and other cutaneous inflammatory events. Preclinical work will focus on a therapeutic approach for promoting TRM responses in conjunction with immune checkpoint inhibition. Overall, this project will define the role of resident memory T cells in the immune response to cancer. By demonstrating a fundamental role for TRM cells in host-wide immunity to cancer, these studies are expected to have a transformative impact on the way that immunotherapies are delivered and evaluated.