Vassiliki Saloura1, Evgeny Izumchenko2, Zhixiang Zuo3, Riyue Bao4, Michael Korzinkin5, Ivan Ozerov5, Alex Zhavoronkov5, David Sidransky6, Atul Bedi6, Mohammad O Hoque6, Hartmut Koeppen7, Michaela K Keck2, Arun Khattri2, Nyall London6, Nikita Kotlov8, Aiman Fatima2, Theodore Vougiouklakis2, Yusuke Nakamura9, Mark Lingen10, Nishant Agrawal11, Peter A Savage10, Stephen Kron12, Justin Kline2, Marcin Kowanetz7, Tanguy Y Seiwert13. 1. Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute. 2. Department of Medicine, University of Chicago, IL, United States. 3. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, China. 4. Department of Pediatrics, University of Chicago, IL, United States; Center for Research Informatics, University of Chicago, IL, United States. 5. Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Rockville, MD, United States. 6. Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States. 7. Genentech, South San Francisco, CA, United States. 8. BostonGene Corporation, Lincoln, MA, United States. 9. Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Japan. 10. Department of Pathology, University of Chicago, IL, United States. 11. Department of Surgery, University of Chicago, IL, United States. 12. Department of Molecular Genetics and Cell Biology, University of Chicago, IL, United States. 13. Department of Medicine, University of Chicago, IL, United States. Electronic address: tseiwert@medicine.bsd.uchicago.edu.
Abstract
OBJECTIVES: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors. MATERIALS AND METHODS: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status. RESULTS: TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications. CONCLUSIONS: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
OBJECTIVES: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors. MATERIALS AND METHODS: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status. RESULTS:TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications. CONCLUSIONS: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.