TY - JOUR
T1 - Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma
T2 - Implications for immunotherapy
AU - Chen, Y. P.
AU - Wang, Y. Q.
AU - Lv, J. W.
AU - Li, Y. Q.
AU - Chua, M. L.K.
AU - Le, Q. T.
AU - Lee, N.
AU - Dimitrios Colevas, A.
AU - Seiwert, T.
AU - Hayes, D. N.
AU - Riaz, N.
AU - Vermorken, J. B.
AU - O'Sullivan, B.
AU - He, Q. M.
AU - Yang, X. J.
AU - Tang, L. L.
AU - Mao, Y. P.
AU - Sun, Y.
AU - Liu, N.
AU - Ma, J.
N1 - Funding Information:
Natural Science Foundation of Guang Dong Province (2017A030312003), National Natural Science Foundation of China (81802707), Health & Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), Innovation Team Development Plan of the Ministry of Education (IRT_17R110), and the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035).
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-c signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-b signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P ¼ 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
AB - Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-c signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-b signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P ¼ 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
KW - Head and neck squamous cell carcinoma
KW - Immune checkpoint blockade
KW - Immune molecular subgroups
KW - Tumor-immune microenvironment
KW - Virtual microdissection
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U2 - 10.1093/annonc/mdy470
DO - 10.1093/annonc/mdy470
M3 - Article
C2 - 30407504
AN - SCOPUS:85060155755
SN - 0923-7534
VL - 30
SP - 68
EP - 75
JO - Annals of Oncology
JF - Annals of Oncology
IS - 1
ER -