Tissue Resident memory T cell responses to cancer

组织驻留记忆(TRM)细胞是机体对感染性病原体免疫的有效介体 周围组织。我们实验室发表的研究现在证实了TRM细胞在免疫中的关键作用 致癌。我们证明了免疫疗法诱导的CD8 TRM细胞介导了皮肤对黑色素瘤的免疫， 而自身免疫性白癜风是产生这些持久保护的TRM细胞的关键宿主要求。白癜风 长期以来一直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友好的利基环境，这些T细胞提供持久的、保护性的、 抗肿瘤免疫。我们假设外周有不同的功能记忆T细胞 白癜风和其他疾病的小鼠和黑色素瘤患者的持久肿瘤免疫是以组织为基础的 皮肤炎症事件。我们的第一个具体目标是确定TRM细胞对 转移性肿瘤保护。患有白癜风的小鼠也能保持对肺转移的保护，我们的 初步数据显示，白癜风小鼠肺中有明显的肿瘤特异性TRM细胞群。我们会 测试肺TRM细胞和淋巴样TEM细胞共同防止转移性黑色素瘤生长的假设， 并定义了肺和皮肤TRM细胞的核心转录特征。我们的第二个具体目标将是定义 皮肤中保护性TRM召回反应的肿瘤抗原特异性。我们的数据显示，白癜风患者的TRM细胞- 受影响的皮肤具有黑素细胞/黑色素瘤共同抗原的特异性，以及肿瘤特异性的模型。 抗原。我们将确定抗原识别如何影响T细胞功能和对TRM利基的竞争， 并检验这样一种假设，即对肿瘤/自身抗原和新抗原都具有特异性的TRM细胞介导 皮肤黑色素瘤和非黑色素瘤的排斥反应。最后，我们的第三个具体目标将是确定 抗原非相关皮肤炎症在促进黑色素瘤TRM反应中的作用。我们将测试 与黑素细胞无关的皮肤炎症可以通过以下途径产生黑色素瘤特异性TRM细胞的假说 评估患有白癜风和其他皮肤的黑色素瘤患者皮肤活检中TRM细胞的反应 炎症性事件。临床前工作将集中在一种促进TRM反应的治疗方法上 结合免疫检查点抑制。总体而言，该项目将定义驻留内存T的角色 细胞参与对癌症的免疫反应。通过展示TRM细胞在宿主范围内的基础作用 对癌症的免疫力，这些研究预计将对 提供和评估免疫疗法。

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.