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Abstract：
UNASSIGNED: To evaluate whether expanded tumor-infiltrating lymphocytes (TILs) can be obtained from primary uveal melanoma (UM) for potential use as adjuvant treatment in patients at risk of developing metastatic disease.
UNASSIGNED: Experimental research study.
UNASSIGNED: Freshly obtained primary UM from 30 patients.
UNASSIGNED: Three different methods were used to expand TILs: (1) direct culture from small fragments of fresh tumor tissue, (2) single-cell tissue preparation by enzymatic digestion and subsequent enrichment of mononuclear cells, and (3) selection of CD3+ T cells using magnetic beads. Surface expression of costimulatory and inhibitory T-cell markers and T-cell reactivity against autologous tumor cells was assessed. Clinical, histopathologic, genetic, and immunologic characteristics of the tumors were compared with the capacity to expand TILs and with their reactivity against autologous tumor cells.
UNASSIGNED: The feasibility of expanding TILs from primary UM, testing their reactivity to autologous UM cells, and evaluating the impact of an immunomodulatory environment.
UNASSIGNED: Direct culture of tumor parts led to successful TIL culture in 4 of 22 tumors (18%), enrichment of mononuclear cells gave rise to TILs in 5 of 12 tumors (42%), while preselection of CD3+ T cells with magnetic beads resulted in TIL expansion in 17 of 25 tumors (68%). In 8 of 17 tumors (47%), the TIL cultures comprised UM-reactive T cells. The presence of UM-reactive T cells among TILs was not related to clinical, histologic, genetic, or immunological tumor characteristics. Interestingly, RNA-Seq analysis showed that approximately half of the UM tumors displayed an increased expression of immunomodulatory molecules related to T-cell suppression, such as galectin 3, programmed death-ligand 1, cytotoxic T-lymphocyte-associated protein 4, indoleamine 2,3-dioxygenase 1, and lymphocyte activating 3, potentially explaining why T cells require optimal removal of tumor components for expansion.
UNASSIGNED: The need to separate TILs from their tumor microenvironment for their successful expansion and the presence of UM-reactive T cells among TILs suggests that these UM-reactive T cells are strongly suppressed in vivo and that UM is immunogenic. These findings indicate that adoptive TIL therapy could be an option as an adjuvant treatment in primary UM patients at high risk of developing metastatic disease.
UNASSIGNED: Experimental research study.
UNASSIGNED: Freshly obtained primary UM from 30 patients.
UNASSIGNED: Three different methods were used to expand TILs: (1) direct culture from small fragments of fresh tumor tissue, (2) single-cell tissue preparation by enzymatic digestion and subsequent enrichment of mononuclear cells, and (3) selection of CD3+ T cells using magnetic beads. Surface expression of costimulatory and inhibitory T-cell markers and T-cell reactivity against autologous tumor cells was assessed. Clinical, histopathologic, genetic, and immunologic characteristics of the tumors were compared with the capacity to expand TILs and with their reactivity against autologous tumor cells.
UNASSIGNED: The feasibility of expanding TILs from primary UM, testing their reactivity to autologous UM cells, and evaluating the impact of an immunomodulatory environment.
UNASSIGNED: Direct culture of tumor parts led to successful TIL culture in 4 of 22 tumors (18%), enrichment of mononuclear cells gave rise to TILs in 5 of 12 tumors (42%), while preselection of CD3+ T cells with magnetic beads resulted in TIL expansion in 17 of 25 tumors (68%). In 8 of 17 tumors (47%), the TIL cultures comprised UM-reactive T cells. The presence of UM-reactive T cells among TILs was not related to clinical, histologic, genetic, or immunological tumor characteristics. Interestingly, RNA-Seq analysis showed that approximately half of the UM tumors displayed an increased expression of immunomodulatory molecules related to T-cell suppression, such as galectin 3, programmed death-ligand 1, cytotoxic T-lymphocyte-associated protein 4, indoleamine 2,3-dioxygenase 1, and lymphocyte activating 3, potentially explaining why T cells require optimal removal of tumor components for expansion.
UNASSIGNED: The need to separate TILs from their tumor microenvironment for their successful expansion and the presence of UM-reactive T cells among TILs suggests that these UM-reactive T cells are strongly suppressed in vivo and that UM is immunogenic. These findings indicate that adoptive TIL therapy could be an option as an adjuvant treatment in primary UM patients at high risk of developing metastatic disease.
摘要：
未经证实：评估是否可以从原发性葡萄膜黑色素瘤（UM）获得扩增的肿瘤浸润淋巴细胞（TIL），作为有发展为转移性疾病风险的患者的辅助治疗的潜在用途。
未经评估：实验研究。
未经批准：从30名患者中获得新的原发性UM。
UNASSIGNED：使用三种不同的方法来扩展TILs：（1）从新鲜肿瘤组织的小片段直接培养，(2)通过酶消化和随后的单个核细胞富集制备单细胞组织,和(3)使用磁珠选择CD3+T细胞。评估了共刺激和抑制性T细胞标志物的表面表达以及针对自体肿瘤细胞的T细胞反应性。临床,组织病理学,遗传,将肿瘤的免疫学特征与扩增TIL的能力及其对自体肿瘤细胞的反应性进行了比较。
未经评估：从主要UM扩展TIL的可行性，测试它们对自体UM细胞的反应，并评估免疫调节环境的影响。
UNASSIGNED：肿瘤部位的直接培养导致22个肿瘤中的4个（18％）成功的TIL培养，单核细胞的富集在12个肿瘤中的5个（42％）中产生TIL，而用磁珠预选CD3+T细胞导致25例肿瘤中的17例(68%)TIL扩增。17个肿瘤中有8个（47%），TIL培养物包含UM反应性T细胞。TIL中UM反应性T细胞的存在与临床无关，组织学，遗传,或免疫学肿瘤特征。有趣的是,RNA-Seq分析显示，大约一半的UM肿瘤显示与T细胞抑制相关的免疫调节分子表达增加，例如半乳糖凝集素3，程序性死亡配体1，细胞毒性T淋巴细胞相关蛋白4，吲哚胺2,3-双加氧酶1和淋巴细胞激活3，这可能解释了为什么T细胞需要最佳去除肿瘤成分才能进行扩增。
UNASSIGNED：需要将TIL与其肿瘤微环境分离以成功扩增，并且TIL中UM反应性T细胞的存在表明，这些UM反应性T细胞在体内受到强烈抑制，并且UM具有免疫原性。这些发现表明，过继性TIL治疗可能是发展为转移性疾病高风险的原发性UM患者的辅助治疗的一种选择。
未经评估：实验研究。
未经批准：从30名患者中获得新的原发性UM。
UNASSIGNED：使用三种不同的方法来扩展TILs：（1）从新鲜肿瘤组织的小片段直接培养，(2)通过酶消化和随后的单个核细胞富集制备单细胞组织,和(3)使用磁珠选择CD3+T细胞。评估了共刺激和抑制性T细胞标志物的表面表达以及针对自体肿瘤细胞的T细胞反应性。临床,组织病理学,遗传,将肿瘤的免疫学特征与扩增TIL的能力及其对自体肿瘤细胞的反应性进行了比较。
未经评估：从主要UM扩展TIL的可行性，测试它们对自体UM细胞的反应，并评估免疫调节环境的影响。
UNASSIGNED：肿瘤部位的直接培养导致22个肿瘤中的4个（18％）成功的TIL培养，单核细胞的富集在12个肿瘤中的5个（42％）中产生TIL，而用磁珠预选CD3+T细胞导致25例肿瘤中的17例(68%)TIL扩增。17个肿瘤中有8个（47%），TIL培养物包含UM反应性T细胞。TIL中UM反应性T细胞的存在与临床无关，组织学，遗传,或免疫学肿瘤特征。有趣的是,RNA-Seq分析显示，大约一半的UM肿瘤显示与T细胞抑制相关的免疫调节分子表达增加，例如半乳糖凝集素3，程序性死亡配体1，细胞毒性T淋巴细胞相关蛋白4，吲哚胺2,3-双加氧酶1和淋巴细胞激活3，这可能解释了为什么T细胞需要最佳去除肿瘤成分才能进行扩增。
UNASSIGNED：需要将TIL与其肿瘤微环境分离以成功扩增，并且TIL中UM反应性T细胞的存在表明，这些UM反应性T细胞在体内受到强烈抑制，并且UM具有免疫原性。这些发现表明，过继性TIL治疗可能是发展为转移性疾病高风险的原发性UM患者的辅助治疗的一种选择。
