The Immune Microenvironment and Neoantigen Landscape of Aggressive Salivary Gland Carcinomas Differ by Subtype.
Adult
Aged
Aged, 80 and over
Antigens, Neoplasm
/ immunology
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
/ analysis
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating
/ immunology
Male
Middle Aged
Mutation
Prognosis
Salivary Gland Neoplasms
/ genetics
Sequence Analysis, RNA
Tumor Microenvironment
/ immunology
Exome Sequencing
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 06 2020
15 06 2020
Historique:
received:
16
11
2019
revised:
14
01
2020
accepted:
11
02
2020
pubmed:
16
2
2020
medline:
14
9
2021
entrez:
16
2
2020
Statut:
ppublish
Résumé
Salivary gland carcinomas (SGC) 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 (RNA-seq) in 76 tumors representing the three 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.
Identifiants
pubmed: 32060100
pii: 1078-0432.CCR-19-3758
doi: 10.1158/1078-0432.CCR-19-3758
pmc: PMC7918996
mid: NIHMS1562957
doi:
Substances chimiques
Antigens, Neoplasm
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2859-2870Subventions
Organisme : NCI NIH HHS
ID : R01 CA205426
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232097
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE027738
Pays : United States
Organisme : NIDCR NIH HHS
ID : K08 DE024774
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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