Y-P Chen1, Y-Q Wang1, J-W Lv1, Y-Q Li1, M L K Chua2, Q-T Le3, N Lee4, A Dimitrios Colevas5, T Seiwert6, D N Hayes7, N Riaz4, J B Vermorken8, B O'Sullivan9, Q-M He1, X-J Yang1, L-L Tang1, Y-P Mao10, Y Sun1, N Liu11, J Ma12. 1. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China, Guangzhou; Collaborative Innovation Center for Cancer Medicine, Guangzhou; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China. 2. Division of Radiation Oncology, National Cancer Centre, Singapore; Oncology Academic Clinical Programme Duke-NUS Medical School, Singapore. 3. Department of Radiation Oncology, Stanford University, Stanford. 4. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York. 5. Division of Oncology, Department of Medicine, Stanford University, Stanford. 6. Department of Medicine, The University of Chicago, Chicago. 7. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, USA. 8. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium. 9. Ontario Cancer Institute, University Health Network, Toronto, Canada. 10. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China, Guangzhou; Collaborative Innovation Center for Cancer Medicine, Guangzhou; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China; Department of Radiation Oncology, University of Michigan, Ann Arbor. 11. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China, Guangzhou; Collaborative Innovation Center for Cancer Medicine, Guangzhou; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: liun1@sysucc.org.cn. 12. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China, Guangzhou; Collaborative Innovation Center for Cancer Medicine, Guangzhou; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People's Republic of China. Electronic address: majun2@mail.sysu.edu.cn.
Abstract
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-γ 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-β 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 = 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.
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-γ 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-β 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 = 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.