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Article ; Online: Immune suppressive checkpoint interactions in the tumour microenvironment of primary liver cancers.

Zhou, Guoying / Boor, Patrick P C / Bruno, Marco J / Sprengers, Dave / Kwekkeboom, Jaap

2021 Volume 126, Issue 1, Page(s) 10–23

Abstract: Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer-hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-are ... ...

Abstract	Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer-hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-are very limited. HCC and CCA are immunogenic cancers, but effective immune-mediated tumour control is prevented by their immunosuppressive tumour microenvironment. Despite the critical involvement of key co-inhibitory immune checkpoint interactions in immunosuppression in liver cancer, only a minority of patients with HCC respond to monotherapy using approved checkpoint inhibitor antibodies. To develop effective (combinatorial) therapeutic immune checkpoint strategies for liver cancer, in-depth knowledge of the different mechanisms that contribute to intratumoral immunosuppression is needed. Here, we review the co-inhibitory pathways that are known to suppress intratumoral T cells in HCC and CCA. We provide a detailed description of insights from preclinical studies in cellular crosstalk within the tumour microenvironment that results in interactions between co-inhibitory receptors on different T-cell subsets and their ligands on other cell types, including tumour cells. We suggest alternative immune checkpoints as promising targets, and draw attention to the possibility of combined targeting of co-inhibitory and co-stimulatory pathways to abrogate immunosuppression.
MeSH term(s)	Bile Duct Neoplasms/drug therapy ; Bile Duct Neoplasms/immunology ; Bile Duct Neoplasms/pathology ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/pathology ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/immunology ; Cholangiocarcinoma/pathology ; Clinical Trials as Topic ; Humans ; Immune Checkpoint Proteins/immunology ; Immune Checkpoint Proteins/metabolism ; Immunosuppression Therapy/methods ; Immunotherapy/methods ; Liver Neoplasms/drug therapy ; Liver Neoplasms/immunology ; Liver Neoplasms/pathology ; Tumor Microenvironment
Chemical Substances	Immune Checkpoint Proteins
Language	English
Publishing date	2021-08-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-021-01453-3
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Article: Cancer Cell B7-H3 Expression Is More Prevalent in the Pancreato-Biliary Subtype of Ampullary Cancer Than in Pancreatic Cancer.

Geerdes, Emma E / Sideras, Kostandinos / Aziz, M Hosein / van Eijck, Casper H / Bruno, Marco J / Sprengers, Dave / Boor, Patrick P C / Kwekkeboom, Jaap

Frontiers in oncology

2021 Volume 11, Page(s) 615691

Abstract: B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological ... ...

Abstract	B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological relevance of B7-H3 expression in pancreatic cancer is unclear, while there are no data on B7-H3 expression in ampullary cancer. We aimed to compare intra-tumoral B7-H3 expression between these two closely related cancer types and analyze its association with post-surgical disease course. B7-H3 expression levels were determined by immunohistochemistry in tissue microarrays of resected tumors of 137 pancreatic cancer patients and 83 patients with ampullary cancer of the pancreato-biliary subtype. B7-H3 was more frequently expressed in cancer cells of ampullary cancer patients compared to pancreatic cancer patients (51%
Language	English
Publishing date	2021-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.615691
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Article ; Online: Systemic T-cell and humoral responses against cancer testis antigens in hepatocellular carcinoma patients.

Noordam, Lisanne / de Beijer, Monique T A / Mancham, Shanta / Vogler, Isabel / Boor, Patrick P C / de Ruiter, Valeska / Luijten, Robbie / IJzermans, Jan N M / Sahin, Ugur / Bruno, Marco J / Sprengers, Dave / Buschow, Sonja I / Kwekkeboom, Jaap

Oncoimmunology

2022 Volume 11, Issue 1, Page(s) 2131096

Abstract: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide due to high recurrence rates after curative treatment and being frequently diagnosed at an advanced stage. Immune-checkpoint inhibition (ICPI) has yielded ... ...

Abstract	Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide due to high recurrence rates after curative treatment and being frequently diagnosed at an advanced stage. Immune-checkpoint inhibition (ICPI) has yielded impressive clinical successes in a variety of solid cancers, however results in treatment of HCC have been modest. Vaccination could be a promising treatment to synergize with ICPI and enhance response rates. Cancer testis antigens (CTAs) were recently discovered to be widely expressed in HCC and expression in macroscopically tumor-free tissues correlated with recurrence, implying the presence of micro-satellites. To determine whether CTAs are immunogenic in HCC patients, we analyzed systemic T-cell and humoral responses against seven CTAs in 38 HCC patients using a multitude of techniques; flowcytometry, ELISA and whole antigen and peptide stimulation assays. CTA-specific T-cells were detected in all (25/25) analyzed patients, of which most had a memory phenotype but did not exhibit unequivocal signs of chronic stimulation or recent antigen encounter. Proliferative CD4
MeSH term(s)	CD8-Positive T-Lymphocytes ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/therapy ; Granzymes/metabolism ; Humans ; Immune Checkpoint Inhibitors ; Immunoglobulin G/metabolism ; Interleukin-2/metabolism ; Liver Neoplasms/therapy ; Male ; Peptides/metabolism ; Testis/metabolism ; Testis/pathology
Chemical Substances	Immune Checkpoint Inhibitors ; Immunoglobulin G ; Interleukin-2 ; Peptides ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2022-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2022.2131096
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Article ; Online: Immunopeptidome of hepatocytes isolated from patients with HBV infection and hepatocellular carcinoma.

de Beijer, Monique T A / Bezstarosti, Karel / Luijten, Robbie / Doff, Wouter A S / Boor, Patrick P C / Pieterman, Roel F A / Bouzid, Rachid / Biesta, Paula J / Ijzermans, Jan N M / Doukas, Michail / de Man, Robert A / Woltman, Andrea M / Demmers, Jeroen A A / Buschow, Sonja I

JHEP reports : innovation in hepatology

2022 Volume 4, Issue 11, Page(s) 100576

Abstract: Background & aims: Antigen-specific immunotherapy is a promising strategy to treat HBV infection and hepatocellular carcinoma (HCC). To facilitate killing of malignant and/or infected hepatocytes, it is vital to know which T cell targets are presented ... ...

Abstract	Background & aims: Antigen-specific immunotherapy is a promising strategy to treat HBV infection and hepatocellular carcinoma (HCC). To facilitate killing of malignant and/or infected hepatocytes, it is vital to know which T cell targets are presented by human leucocyte antigen (HLA)-I complexes on patient-derived hepatocytes. Here, we aimed to reveal the hepatocyte-specific HLA-I peptidome with emphasis on peptides derived from HBV proteins and tumour-associated antigens (TAA) to guide development of antigen-specific immunotherapy. Methods: Primary human hepatocytes were isolated with high purity from (HBV-infected) non-tumour and HCC tissues using a newly designed perfusion-free procedure. Hepatocyte-derived HLA-bound peptides were identified by unbiased mass spectrometry (MS), after which source proteins were subjected to Gene Ontology and pathway analysis. HBV antigen and TAA-derived HLA peptides were searched for using targeted MS, and a selection of peptides was tested for immunogenicity. Results: Using unbiased data-dependent acquisition (DDA), we acquired a high-quality HLA-I peptidome of 2 × 10 Conclusions: We present a first HLA-I immunopeptidome of isolated primary human hepatocytes, devoid of immune cells. Identified HBV-derived and TAA-derived peptides directly aid development of antigen-specific immunotherapy for chronic HBV infection and HCC. The described methodology can also be applied to personalise immunotherapeutic treatment of liver diseases in general. Lay summary: Immunotherapy that aims to induce immune responses against a virus or tumour is a promising novel treatment option to treat chronic HBV infection and liver cancer. For the design of successful therapy, it is essential to know which fragments (
Language	English
Publishing date	2022-09-05
Publishing country	Netherlands
Document type	Journal Article
ISSN	2589-5559
ISSN (online)	2589-5559
DOI	10.1016/j.jhepr.2022.100576
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Article: Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma.

Ge, Zhouhong / Helmijr, Jean C A / Jansen, Maurice P H M / Boor, Patrick P C / Noordam, Lisanne / Peppelenbosch, Maikel / Kwekkeboom, Jaap / Kraan, Jaco / Sprengers, Dave

Translational oncology

2021 Volume 14, Issue 7, Page(s) 101073

Abstract: Background and aims: Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine ... ...

Abstract	Background and aims: Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients. Methods: Twenty-six mostly advanced HCC patients were enrolled. 30 mL peripheral blood from each patient was obtained. CellSearch system was used for CTC detection. A sequencing panel covering 14 cancer-relevant genes was used to identify oncogenic mutations. TERT promoter C228T and C250T mutations were determined by droplet digital PCR. Results: CTCs were detected in 27% (7/26) of subjects but at low numbers (median: 2 cells, range: 1-15 cells) and ctDNA in 77% (20/26) of patients. Mutations in ctDNA were identified in several genes: TERT promoter C228T (77%, 20/26), TP53 (23%, 6/26), CTNNB1 (12%, 3/26), PIK3CA (12%, 3/26) and NRAS (4%, 1/26). The TERT C228T mutation was present in all patients with one or more ctDNA mutations, or detectable CTCs. The TERT C228T and TP53 mutations detected in ctDNA were present at higher levels in matched primary HCC tumor tissue. The maximal variant allele frequency (VAF) of ctDNA was linearly correlated with largest tumor size and AFP level (Log10). CtDNA (or TERT C228T) positivity was associated with macrovascular invasion, and positivity of ctDNA (or TERT C228T) or CTCs (≥ 2) correlated with poor patient survival. Conclusions: Oncogenic mutations could be detected in ctDNA from advanced HCC patients. CtDNA analysis may serve as a promising liquid biopsy to identify druggable mutations.
Language	English
Publishing date	2021-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2443840-6
ISSN	1936-5233
ISSN	1936-5233
DOI	10.1016/j.tranon.2021.101073
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Article ; Online: HHLA2 is expressed in pancreatic and ampullary cancers and increased expression is associated with better post-surgical prognosis.

Boor, Patrick P C / Sideras, Kostandinos / Biermann, Katharina / Hosein Aziz, M / Levink, Iris J M / Mancham, Shanta / Erler, Nicole S / Tang, Xudong / van Eijck, Casper H / Bruno, Marco J / Sprengers, Dave / Zang, Xingxing / Kwekkeboom, Jaap

British journal of cancer

2020 Volume 122, Issue 8, Page(s) 1211–1218

Abstract: Background: HHLA2 is a recently discovered member of the B7-family of immune checkpoint molecules with limited expression in normal tissues but overexpression in several types of cancer. The aim was to determine the expression, prevalence and biological ...

Abstract	Background: HHLA2 is a recently discovered member of the B7-family of immune checkpoint molecules with limited expression in normal tissues but overexpression in several types of cancer. The aim was to determine the expression, prevalence and biological relevance of HHLA2 protein expression in two closely related human cancer types, namely pancreatic cancer and ampullary cancer. Methods: HHLA2 expression levels were retrospectively determined by immunohistochemistry in tissue micro-arrays of surgically resected tumours of 122 pancreatic cancer patients and 72 patients with ampullary cancer of the pancreato-biliary subtype. Results: HHLA2 was expressed at variable levels by tumour cells in 67% of pancreatic tumours and 93% of ampullary tumours. In the combined cohort high tumoural HHLA2 expression levels were significantly associated with delayed cancer recurrence and improved post-operative cancer-specific survival. The association of HHLA2 expression with cancer-specific survival and recurrence was statistically significant for the pancreatic cancer subgroup while a similar trend was found for the ampullary cancer subgroup. In multivariable analysis together with clinicopathologic characteristics, higher HHLA2 expression was an independent predictor of cancer-specific survival. Conclusion: The wide expression of HHLA2 in tumour cells and its association with cancer recurrence and patient survival suggest that HHLA2 represents a relevant immune checkpoint molecule in pancreatic and ampullary cancers.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Ampulla of Vater ; Common Bile Duct Neoplasms/chemistry ; Common Bile Duct Neoplasms/mortality ; Common Bile Duct Neoplasms/pathology ; Common Bile Duct Neoplasms/surgery ; Female ; Humans ; Immunoglobulins/analysis ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Pancreatic Neoplasms/chemistry ; Pancreatic Neoplasms/mortality ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/surgery ; Prognosis ; Retrospective Studies
Chemical Substances	HHLA2 protein, human ; Immunoglobulins
Language	English
Publishing date	2020-02-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-0755-4
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Article: Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma.

Noordam, Lisanne / Ge, Zhouhong / Özturk, Hadiye / Doukas, Michail / Mancham, Shanta / Boor, Patrick P C / Campos Carrascosa, Lucia / Zhou, Guoying / van den Bosch, Thierry P P / Pan, Qiuwei / IJzermans, Jan N M / Bruno, Marco J / Sprengers, Dave / Kwekkeboom, Jaap

Cancers

2021 Volume 13, Issue 10

Abstract: High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims ... ...

Abstract	High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.
Language	English
Publishing date	2021-05-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13102499
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Article ; Online: TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8

Ge, Zhouhong / Zhou, Guoying / Campos Carrascosa, Lucia / Gausvik, Erik / Boor, Patrick P C / Noordam, Lisanne / Doukas, Michael / Polak, Wojciech G / Terkivatan, Türkan / Pan, Qiuwei / Takkenberg, R Bart / Verheij, Joanne / Erdmann, Joris I / IJzermans, Jan N M / Peppelenbosch, Maikel P / Kraan, Jaco / Kwekkeboom, Jaap / Sprengers, Dave

Cellular and molecular gastroenterology and hepatology

2021 Volume 12, Issue 2, Page(s) 443–464

Abstract: Background & aims: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of ...

Abstract	Background & aims: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). Methods: Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. Results: TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1 Conclusions: Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8
MeSH term(s)	Aged ; Antigen-Presenting Cells/immunology ; Antigens, CD/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Hepatocellular/immunology ; Cell Proliferation ; Down-Regulation ; Female ; HMGB Proteins/metabolism ; Hep G2 Cells ; Humans ; Liver Neoplasms/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Receptors, Immunologic/antagonists & inhibitors ; Receptors, Immunologic/metabolism ; T-Lymphocytes, Regulatory/immunology ; Thymocytes/immunology ; Up-Regulation
Chemical Substances	Antigens, CD ; HMGB Proteins ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Receptors, Immunologic ; TIGIT protein, human
Language	English
Publishing date	2021-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2819778-1
ISSN	2352-345X ; 2352-345X
ISSN (online)	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2021.03.003
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Article ; Online: Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells.

Zhou, Guoying / Lieshout, Ruby / van Tienderen, Gilles S / de Ruiter, Valeska / van Royen, Martin E / Boor, Patrick P C / Magré, Luc / Desai, Jyaysi / Köten, Kübra / Kan, Yik Yang / Ge, Zhouhong / Campos Carrascosa, Lucia / Geuijen, Cecile / Sprengers, Dave / van der Laan, Luc J W / Verstegen, Monique M A / Kwekkeboom, Jaap

British journal of cancer

2022 Volume 127, Issue 4, Page(s) 649–660

Abstract: Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is being explored to improve cholangiocarcinoma (CCA) therapy. However, it remains difficult to predict which ICI will be effective for individual patients. Therefore, the aim of this ... ...

Abstract	Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is being explored to improve cholangiocarcinoma (CCA) therapy. However, it remains difficult to predict which ICI will be effective for individual patients. Therefore, the aim of this study is to develop a co-culture method with patient-derived CCA organoids and immune cells, which could represent anti-cancer immunity in vitro. Methods: CCA organoids were co-cultured with peripheral blood mononuclear cells or T cells. Flow cytometry, time-lapse confocal imaging for apoptosis, and quantification of cytokeratin 19 fragment (CYFRA) release were applied to analyse organoid and immune cell behaviour. CCA organoids were also cultured in immune cell-conditioned media to analyse the effect of soluble factors. Results: The co-culture system demonstrated an effective anti-tumour organoid immune response by a decrease in live organoid cells and an increase in apoptosis and CYFRA release. Interpatient heterogeneity was observed. The cytotoxic effects could be mediated by direct cell-cell contact and by release of soluble factors, although soluble factors only decreased viability in one organoid line. Conclusions: In this proof-of-concept study, a novel CCA organoid and immune cell co-culture method was established. This can be the first step towards personalised immunotherapy for CCA by predicting which ICIs are most effective for individual patients.
MeSH term(s)	Bile Duct Neoplasms ; Bile Ducts, Intrahepatic/pathology ; Cholangiocarcinoma ; Humans ; Leukocytes, Mononuclear/metabolism ; Organoids ; T-Lymphocytes/pathology
Language	English
Publishing date	2022-05-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-01839-x
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Article ; Online: JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.

Boor, Patrick P C / de Ruiter, Petra E / Asmawidjaja, Patrick S / Lubberts, Erik / van der Laan, Luc J W / Kwekkeboom, Jaap

Translational research : the journal of laboratory and clinical medicine

2017 Volume 188, Page(s) 67–79

Abstract: Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased ... ...

Abstract	Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment.
MeSH term(s)	Apoptosis/physiology ; Cell Line, Tumor ; Dendritic Cells/drug effects ; Dendritic Cells/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Hepacivirus/physiology ; Humans ; Interferon-alpha/genetics ; Interferon-alpha/metabolism ; Interleukin-3/genetics ; Interleukin-3/metabolism ; Piperidines/administration & dosage ; Piperidines/pharmacology ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrimidines/administration & dosage ; Pyrimidines/pharmacology ; Pyrroles/administration & dosage ; Pyrroles/pharmacology ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Virus Replication
Chemical Substances	Interferon-alpha ; Interleukin-3 ; Piperidines ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-2 ; Pyrimidines ; Pyrroles ; STAT Transcription Factors ; tofacitinib (87LA6FU830)
Language	English
Publishing date	2017-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2016.11.006
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