The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype.
The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype.
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DOI：
10.1158/1078-0432.ccr-19-3758
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发表时间：
2020-06-15
期刊：
影响因子：
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通讯作者：
Morris LGT
中科院分区：
文献类型：
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作者：
Linxweiler M;Kuo F;Katabi N;Lee M;Nadeem Z;Dalin MG;Makarov V;Chowell D;Dogan S;Ganly I;Hakimi AA;Wong RJ;Riaz N;Ho AL;Chan TA;Morris LGT
涎腺癌是一种罕见的侵袭性肿瘤，具有高复发率和远处转移。这些因素，以及缺乏积极的全身治疗，导致临床结果不佳。免疫检查点阻断的应答率一直很低，尽管临床数据仍然很少。为了提高治疗效果，需要更全面地了解相关的分子改变和免疫过程。为了表征SGCs的免疫微环境和新抗原景观，我们在代表3种最致命组织学的76种肿瘤中进行了RNA测序（RNAseq）：腺样囊性癌（ACC）、肌上皮癌（MECA）和唾液腺导管癌（SDC）。我们分析了转录组学特征、肿瘤浸润免疫细胞群和T细胞活化/功能障碍的测量。在37例同样接受外显子组测序的病例中，我们分析了体细胞突变和新抗原。SDC表现出高水平的免疫浸润，相应的更高水平的T细胞功能障碍和更高的突变负荷。相比之下，ACC的特征在于免疫排斥微环境，M2极化巨噬细胞和髓源性抑制细胞的存在，以及非常低的突变负荷。MECA更加异质，免疫低和免疫高表型都有代表。在所有SGCs中，免疫浸润水平与突变和融合衍生的新抗原以及侵袭性临床行为相关。这些发现为SGCs的免疫微环境和新抗原景观提供了新的见解，表明免疫逃逸机制似乎因组织学而异。这些数据表明了潜在的免疫脆弱性，并可能有助于指导这些难以治疗的癌症的精确免疫治疗的下一步研究。
Salivary gland carcinomas (SGCs) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed. To characterize the immune microenvironment and neoantigen landscape of SGCs, we performed RNA sequencing (RNAseq) in 76 tumors representing the 3 most lethal histologies: adenoid cystic carcinoma (ACC), myoepithelial carcinoma (MECA), and salivary duct carcinoma (SDC). We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T cell activation/dysfunction. In 37 cases also undergoing exome sequencing, we analyzed somatic mutations and neoantigens. SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T cell dysfunction, and higher mutational load. In contrast, ACCs were characterized by an immune-excluded microenvironment, the presence of M2-polarized macrophages and myeloid-derived suppressor cells, and very low mutational load. MECAs were more heterogeneous, with both immune-low and immune-high phenotypes represented. Across all SGCs, levels of immune infiltration were associated with mutation- and fusion-derived neoantigens, and with aggressive clinical behavior. These findings provide new insights into the immune microenvironment and neoantigen landscape of SGCs, showing that mechanisms of immune escape appear to differ by histology. These data nominate potential immunologic vulnerabilities and may help guide the next steps of investigation in precision immunotherapy for these difficult-to-treat cancers.