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.
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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
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Acknowledgements
We thank the patients and their families for participation in this research. Writing of the manuscript was supported by 4SC, Planegg-Martinsried (Germany).
Funding
This work was supported by the German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, DKTK).
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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.
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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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Ugurel, S., Spassova, I., Wohlfarth, J. et al. 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. Cancer Immunol Immunother 68, 983–990 (2019). https://doi.org/10.1007/s00262-019-02341-9
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DOI: https://doi.org/10.1007/s00262-019-02341-9