Immune profiles in primary squamous cell carcinoma of the head and neck

Vassiliki Saloura, Evgeny Izumchenko, Zhixiang Zuo, R. Bao, Michael Korzinkin, Ivan Ozerov, Alex Zhavoronkov, D. Sidransky, Atul Bedi, Mohammad O. Hoque, Hartmut Koeppen, Michaela K. Keck, Arun Khattri, N. London, Nikita Kotlov, A. Fatima, Theodore Vougiouklakis, Yusuke Nakamura, Mark Lingen, Nishant AgrawalPeter A. Savage, Stephen Kron, Justin Kline, Marcin Kowanetz, Tanguy Y. Seiwert

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)77-88
Number of pages12
JournalOral Oncology
Volume96
DOIs
StatePublished - Sep 1 2019

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Neoplasms
Regulatory T-Lymphocytes
Mutation
Macrophages
Carcinoma, squamous cell of head and neck
T-Lymphocytes
Catenins
Tumor Microenvironment
2,3,6-trichloroindophenol
Atlases
Genomics
Chemokines
Immunotherapy
Neck
Biomarkers
Head
Genome
Phenotype
Genes
Therapeutics

Keywords

  • Head and neck cancer
  • Immune checkpoints
  • T-cell inflamed phenotype

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

Cite this

Immune profiles in primary squamous cell carcinoma of the head and neck. / Saloura, Vassiliki; Izumchenko, Evgeny; Zuo, Zhixiang; Bao, R.; Korzinkin, Michael; Ozerov, Ivan; Zhavoronkov, Alex; Sidransky, D.; Bedi, Atul; Hoque, Mohammad O.; Koeppen, Hartmut; Keck, Michaela K.; Khattri, Arun; London, N.; Kotlov, Nikita; Fatima, A.; Vougiouklakis, Theodore; Nakamura, Yusuke; Lingen, Mark; Agrawal, Nishant; Savage, Peter A.; Kron, Stephen; Kline, Justin; Kowanetz, Marcin; Seiwert, Tanguy Y.

In: Oral Oncology, Vol. 96, 01.09.2019, p. 77-88.

Research output: Contribution to journalArticle

Saloura, V, Izumchenko, E, Zuo, Z, Bao, R, Korzinkin, M, Ozerov, I, Zhavoronkov, A, Sidransky, D, Bedi, A, Hoque, MO, Koeppen, H, Keck, MK, Khattri, A, London, N, Kotlov, N, Fatima, A, Vougiouklakis, T, Nakamura, Y, Lingen, M, Agrawal, N, Savage, PA, Kron, S, Kline, J, Kowanetz, M & Seiwert, TY 2019, 'Immune profiles in primary squamous cell carcinoma of the head and neck', Oral Oncology, vol. 96, pp. 77-88. https://doi.org/10.1016/j.oraloncology.2019.06.032
Saloura V, Izumchenko E, Zuo Z, Bao R, Korzinkin M, Ozerov I et al. Immune profiles in primary squamous cell carcinoma of the head and neck. Oral Oncology. 2019 Sep 1;96:77-88. https://doi.org/10.1016/j.oraloncology.2019.06.032
Saloura, Vassiliki ; Izumchenko, Evgeny ; Zuo, Zhixiang ; Bao, R. ; Korzinkin, Michael ; Ozerov, Ivan ; Zhavoronkov, Alex ; Sidransky, D. ; Bedi, Atul ; Hoque, Mohammad O. ; Koeppen, Hartmut ; Keck, Michaela K. ; Khattri, Arun ; London, N. ; Kotlov, Nikita ; Fatima, A. ; Vougiouklakis, Theodore ; Nakamura, Yusuke ; Lingen, Mark ; Agrawal, Nishant ; Savage, Peter A. ; Kron, Stephen ; Kline, Justin ; Kowanetz, Marcin ; Seiwert, Tanguy Y. / Immune profiles in primary squamous cell carcinoma of the head and neck. In: Oral Oncology. 2019 ; Vol. 96. pp. 77-88.
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AU - Saloura, Vassiliki

AU - Izumchenko, Evgeny

AU - Zuo, Zhixiang

AU - Bao, R.

AU - Korzinkin, Michael

AU - Ozerov, Ivan

AU - Zhavoronkov, Alex

AU - Sidransky, D.

AU - Bedi, Atul

AU - Hoque, Mohammad O.

AU - Koeppen, Hartmut

AU - Keck, Michaela K.

AU - Khattri, Arun

AU - London, N.

AU - Kotlov, Nikita

AU - Fatima, A.

AU - Vougiouklakis, Theodore

AU - Nakamura, Yusuke

AU - Lingen, Mark

AU - Agrawal, Nishant

AU - Savage, Peter A.

AU - Kron, Stephen

AU - Kline, Justin

AU - Kowanetz, Marcin

AU - Seiwert, Tanguy Y.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

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