Identification of an Immunogenic Subset of Metastatic Uveal Melanoma.
Identification of an Immunogenic Subset of Metastatic Uveal Melanoma.
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DOI：
10.1158/1078-0432.ccr-15-2294
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发表时间：
2016-05-01
期刊：
影响因子：
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通讯作者：
Kammula US
中科院分区：
文献类型：
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作者：
Rothermel LD;Sabesan AC;Stephens DJ;Chandran SS;Paria BC;Srivastava AK;Somerville R;Wunderlich JR;Lee CC;Xi L;Pham TH;Raffeld M;Jailwala P;Kasoji M;Kammula US
葡萄膜黑色素瘤（UM）是一种罕见的黑色素瘤变体，一旦发生转移，就没有有效的治疗方法。虽然在转移性皮肤黑色素瘤（CM）中可以通过增强天然存在的抗肿瘤T细胞应答的免疫疗法实现持久的癌症消退，但这些治疗对转移性UM的作用仍不清楚。我们试图确定这两种黑色素瘤变体的相对免疫原性，并确定是否存在针对UM的内源性抗肿瘤免疫应答。我们通过手术从UM（n=16）和CM（n=35）患者获得肝转移瘤，并使用临床放射学、组织病理学、免疫测定和全外显子组测序比较其各自的肿瘤细胞群及其浸润性T细胞（TIL）的属性。尽管有共同的黑素细胞谱系，UM和CM转移不同的黑素含量，肿瘤分化抗原表达，和体细胞突变谱。从这些不同形式的黑色素瘤扩增的TIL培养物的免疫学分析显示CM TIL主要由CD8+ T细胞组成，而UM TIL是CD4+占优势的。与UM TIL相比，CM TIL对自体肿瘤的反应性显著更高。然而，我们从UM患者的亚组中鉴定了TIL，其具有与CM TIL相当的强度的稳健的抗肿瘤反应性。有趣的是，亲代肿瘤中黑色素沉着的缺乏与高反应性UM TIL的产生强烈相关。UM转移的这种免疫原性组的发现应该促使临床努力确定携带这些独特肿瘤的患者是否可以从利用内源性抗肿瘤T细胞群的免疫疗法中获益。
Uveal melanoma (UM) is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma (CM) with immunotherapies that augment naturally existing anti-tumor T cell responses, the role of these treatments for metastatic UM remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous anti-tumor immune responses exist against UM. We surgically procured liver metastases from UM (n=16) and CM (n=35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays and whole exomic sequencing. Despite having common melanocytic lineage, UM and CM metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed CM TIL were predominantly composed of CD8+ T cells, while UM TIL were CD4+ dominant. Reactivity against autologous tumor was significantly greater in CM TIL compared to UM TIL. However, we identified TIL from a subset of UM patients which had robust anti-tumor reactivity comparable in magnitude to CM TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive UM TIL. The discovery of this immunogenic group of UM metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous anti-tumor T cell populations.