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MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series

  • Selma Ugurel
  • Ivelina Spassova
  • Jonas Wohlfarth
  • Christina Drusio
  • Angela Cherouny
  • Anita Melior
  • Antje Sucker
  • Lisa Zimmer
  • Cathrin Ritter
  • Dirk Schadendorf
  • Jürgen C. BeckerEmail author
Original Article

Abstract

Background

Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8+ T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo.

Case presentations

We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.

Results and conclusion

Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8+ T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.

Keywords

Merkel cell carcinoma HDAC inhibitor Immunotherapy HLA class-I Infiltration 

Abbreviations

APM

Antigen processing machinery

B2 M

β2 microglobulin

Ct

Cycle threshold

CT

Computed tomography

FFPE

Formalin-fixed paraffin-embedded

HDAC

Histone deacetylase

HDACi

Histone deacetylase inhibitor

IT-CD8+

Intratumoral CD8+ T cells

LINE

Long interspersed nuclear element

LMP

Low-molecular-weight proteins

MCC

Merkel cell carcinoma

MCPyV

Merkel cell polyomavirus

PET-CT

Positron-emission tomography and computed tomography

qRT-PCR

Quantitative real-time-PCR

TAP

Transporter associated with antigen processing

\( 2^{{ - \Delta \Delta C_{\text{t}} }} \)

Method, comparative Ct method

Notes

Acknowledgements

We thank the patients and their families for participation in this research. Writing of the manuscript was supported by 4SC, Planegg-Martinsried (Germany).

Author contributions

SU and JCB designed experiments, acquired, analyzed and interpreted the data, and wrote and revised the manuscript. IS, AC, AM, and CR performed experiments, analyzed, and interpreted the data. JW, CD, AS, LZ, and DS participated in the design of experiments, interpretation of the data, and writing of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, DKTK).

Compliance with ethical standards

Conflict of interest

Selma Ugurel declares research support from medac and Bristol-Myers Squibb, speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dome, and Roche, and travel support from Bristol-Myers Squibb, medac, Merck Sharp & Dome, and Roche. Jonas Wohlfarth is an intern at 4SC. Lisa Zimmer has served as consultant or/and has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dome, GlaxoSmithKline, Novartis, Merck Serono, and travel support from Merck Sharp & Dome, Bristol-Myers Squibb, Amgen and Novartis. Dirk Schadendorf has received speaker honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dome, Amgen, Merck Serono and Pierre-Fabre, advisory board honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dome, Amgen, Incyte, Merck Serono and Pierre-Fabre as well as research funding from Novartis and Bristol-Myers Squibb. Jürgen C. Becker has received speaker honoraria from Amgen, Merck Serono, and Pfizer, advisory board honoraria from Amgen, CureVac, eTheRNA, Lytix, Merck Serono, Novartis, Rigontec, and Takeda as well as research funding from Alcedis, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Serono; he also received travel support from 4SC and Incyte. The authors declare that there is no other conflict of interest.

Ethical approval

The investigational procedures were approved by the institutional review board/ethic committee (17-7539-BO; Ethics Committee of the University Duisburg-Essen).

Informed consent

All patients provided informed consent for the scientific work up of the tumor biopsies as well as for the publication of the results in an anonymized way.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Selma Ugurel
    • 1
  • Ivelina Spassova
    • 2
  • Jonas Wohlfarth
    • 3
  • Christina Drusio
    • 1
  • Angela Cherouny
    • 2
  • Anita Melior
    • 2
  • Antje Sucker
    • 1
  • Lisa Zimmer
    • 1
  • Cathrin Ritter
    • 2
    • 4
  • Dirk Schadendorf
    • 1
    • 4
  • Jürgen C. Becker
    • 1
    • 2
    • 4
    Email author
  1. 1.Department of DermatologyUniversity Clinic EssenEssenGermany
  2. 2.Translational Skin Cancer Research (TSCR)University Clinic EssenEssenGermany
  3. 3.University WürzburgWürzburgGermany
  4. 4.German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, DKTK) Partner Site Essen, Deutsches Krebsforschungsinstitut (DKFZ)HeidelbergGermany

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