Molecular Diagnostics

Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response

  • A Correction to this article was published on 22 June 2020



Oropharyngeal cancer (OPC) exhibits diverse immunological properties; however, their implications for immunotherapy are unknown.


We analysed 37 surgically resected and nine recurrent or metastatic anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-treated OPC tumours. OPCs were classified into immune-rich (IR), mesenchymal (MS) and xenobiotic (XB) subtypes based on RNA-sequencing data.


All IR type tumours were human papillomavirus (HPV) positive, most XB types were HPV negative, and MS types showed mixed HPV status. The IR type showed an enriched T cell exhaustion signature with PD-1+ CD8+ T cells and type I macrophages infiltrating the tumour nest on multiplex immunohistochemistry. The MS type showed an exclusion of CD8+ T cells from the tumour nest and high MS and tumour growth factor-β signatures. The XB type showed scant CD8+ T cell infiltration and focal CD73 expression. The IR type was associated with a favourable response signature during anti-PD-1/PD-L1 therapy and showed a high APOBEC mutation signature, whereas the MS and XB types showed resistance signature upregulation. Among anti-PD-1/PD-L1-treated OPC patients, the IR type showed a favourable clinical response (3/4 patients), whereas the XB type showed early progression (3/3 patients).


Our analysis classified OPCs into three subtypes with distinct immune microenvironments that are potentially related to the response to anti-PD-1/PD-L1 therapy.

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Fig. 1: Three molecular subtypes of OPC identified by RNA-seq analysis of tumours show different survival outcomes.
Fig. 2: Characterisation of subtype-specific gene signatures.
Fig. 3: Distinct tumour immune microenvironment of OPC subtypes revealed by RNA-seq.
Fig. 4: Distinct immune microenvironment of OPC subtypes revealed by multiplex IHC.
Fig. 5: Analysis of subtype-specific genetic properties by next-generation sequencing of OPC tumour DNA.
Fig. 6: The molecular subtype predicts response to anti-PD-1/PD-L1 therapy in OPC patients.

Change history

  • 22 June 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


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We acknowledge Suyeon Jang for administrating the sample collection and transfer procedures. We also acknowledge Macrogen, Inc. for performing RNA-seq and targeted sequencing experiments.

Author information




M.H.K., J.-H.K., Y.W.K. and H.R.K. conceived the study. J.-H.K. and J.M.L. performed multiplex IHC and HPV PCR experiments and analysed the data. M.H.K., J.W.C., J.M.L., D.J., H.K. and S.W.K. performed bioinformatic analysis. H.C. analysed the PET-CT scan data. M.H.H., S.J.H., S.H.K., E.C.C., D.H.K., Y.M.P., S.O.Y., Y.W.K., B.C.C. and H.R.K. contributed to the sample and clinical data collections. B.C.C. and H.R.K. contributed to the financial and administration support for this study. S.O.Y. contributed to pathological review of tumour tissues. M.H.K., J.W.C., J.-H.K. and H.R.K. wrote the manuscript.

Corresponding author

Correspondence to Hye Ryun Kim.

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Ethics approval and consent to participate

This study was reviewed and approved by the Institutional Review Board of Severance Hospital. Informed consent was obtained from all participants. This study was performed in accordance with the Declaration of Helsinki.

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Not applicable.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This research was supported by the Young Medical Scientist Research Grant through the Deawoong Foundation (DY18111P), by the Bio & Medical Technology Development Programme of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (2017M3A9E8029717, 2017M3A9E9072669, 2019M3A9B6065231) and by a grant from the National R&D Programme for Cancer Control, Ministry of Health and Welfare (HA16C0015). This study was also supported by the Research Foundation of Yonsei University (No. 6-2017-0104).

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Kim, M.H., Kim, J., Lee, J.M. et al. Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response. Br J Cancer 122, 1649–1660 (2020).

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