Head and Neck Squamous Cell Carcinomas Are Characterized by a Stable Immune Signature Within the Primary Tumor Over Time and Space

Wood, Oliver; Clarke, James; Woo, Jeogmin; Mirza, Adal H.; Woelk, Christopher H.; Thomas, Gareth J.; Vijayanand, Pandurangan; King, Emma V.; Ottensmeier, Christian

doi:10.1158/1078-0432.ccr-17-0373

Cited by 24 publications

(23 citation statements)

References 33 publications

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“…In this study we have used an immune signature reported by Wood et al, due to its high stability in HNSCC specimens (Suppl. Figure 3b) [26]. We found that low expression of TMPRSS2 signi cantly associates with low immune signature in TCGA HNSCC patients' cohort ( Fig.…”

Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 60%

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

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Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

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Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 60%

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Fig. 3 b) [ 28 ]. We found that low expression of TMPRSS2 significantly associates with low immune signature in TCGA HNSCC patients’ cohort (Fig.…”

Section: Resultsmentioning

confidence: 99%

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. Methods The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. Results TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. Conclusions Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

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“…Multiplex immunohistochemistry (MxIHC) was performed on FFPE samples from the HNSCC cohort (Bulk RNA-seq and analysis; ref. 38), where tissue was available (n ¼ 16; Research Ethics Committee reference 09/H0501/90). Staining and image processing was performed as previously with minor alterations (41).…”

Section: Histologic Analysismentioning

confidence: 99%

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors

et al. 2020

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Determining mechanisms of resistance to aPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), aPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8 þ T cells from tumors (not CD4 þ T cells or macrophages); CD8 þ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8 þ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8 þ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFb1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8 þ T-cell infiltration, overcoming the exclusion effect; TGFb1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAFrich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. Significance: NOX4 is critical for maintaining the immunesuppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAFmediated CD8 þ T-cell exclusion.

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Head and Neck Squamous Cell Carcinomas Are Characterized by a Stable Immune Signature Within the Primary Tumor Over Time and Space

Cited by 24 publications

References 33 publications

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors

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