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Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1

K. Hladíková, S. Partlová, V. Koucký, J. Bouček, JF. Fonteneau, M. Zábrodský, R. Tachezy, M. Grega, R. Špíšek, A. Fialová,

. 2018 ; 82 (-) : 75-82. [pub] 20180526

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19045410

Grantová podpora
NV16-28600A MZ0 CEP - Centrální evidence projektů

BACKGROUND: Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-associated carcinomas of the head and neck were reported to have a better clinical outcome than patients with HPV-negative tumors. Because HPV16 E6 and E7 oncoproteins are highly immunogenic and constitutively expressed, HPV-specific T cell immunity may play the key role in improving the prognosis of these patients. METHODS: Tumor-derived T cells were expanded in high levels of IL-2 and stimulated with HPV16 E6/E7 peptides in the presence or absence of anti-PD-1 monoclonal antibody nivolumab and soluble Tim-3. RESULTS: HPV16-specific tumor-infiltrating T cells were present in 73.1% of HPV-associated oropharyngeal tumors. HPV16 specific CD8+ TILs were able to produce IFNγ upon specific stimulation and predominantly expressed PD-1 but not Tim-3. Specific IFNγ production was further enhanced after a blockade of both PD-1 and Tim-3 pathways but not after a PD-1 blockade alone. Additionally, the specific stimulation of anti-HPV16 CD8+ T cells suppressed Tim-3 upregulation after the PD-1 blockade. CONCLUSION: Our data provide the rationale for combination cancer immunotherapy approaches, including the dual blockade of PD-1 and Tim-3 and, potentially, the use of HPV16-directed therapeutic vaccines.

Citace poskytuje Crossref.org

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$a Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1 / $c K. Hladíková, S. Partlová, V. Koucký, J. Bouček, JF. Fonteneau, M. Zábrodský, R. Tachezy, M. Grega, R. Špíšek, A. Fialová,
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$a BACKGROUND: Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-associated carcinomas of the head and neck were reported to have a better clinical outcome than patients with HPV-negative tumors. Because HPV16 E6 and E7 oncoproteins are highly immunogenic and constitutively expressed, HPV-specific T cell immunity may play the key role in improving the prognosis of these patients. METHODS: Tumor-derived T cells were expanded in high levels of IL-2 and stimulated with HPV16 E6/E7 peptides in the presence or absence of anti-PD-1 monoclonal antibody nivolumab and soluble Tim-3. RESULTS: HPV16-specific tumor-infiltrating T cells were present in 73.1% of HPV-associated oropharyngeal tumors. HPV16 specific CD8+ TILs were able to produce IFNγ upon specific stimulation and predominantly expressed PD-1 but not Tim-3. Specific IFNγ production was further enhanced after a blockade of both PD-1 and Tim-3 pathways but not after a PD-1 blockade alone. Additionally, the specific stimulation of anti-HPV16 CD8+ T cells suppressed Tim-3 upregulation after the PD-1 blockade. CONCLUSION: Our data provide the rationale for combination cancer immunotherapy approaches, including the dual blockade of PD-1 and Tim-3 and, potentially, the use of HPV16-directed therapeutic vaccines.
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$a Bouček, Jan $u Department of Otorhinolaryngology and Head and Neck Surgery, 1st Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic; Institute of Microbiology ASCR, v.v.i., Vídeňská 1083, 142 20 Prague, Czech Republic.
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$a Fonteneau, Jean-Francois $u CRCINA, INSERM U1232, Université de Nantes, 8 Quai Moncousu, 44007 Nantes, France.
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$a Tachezy, Ruth $u Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Viničná 5, 128 44 Prague, Czech Republic.
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$a Grega, Marek $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Úvalu 84, 150 06 Prague, Czech Republic.
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$a Špíšek, Radek $u Sotio, Jankovcova 1518/2, 170 00 Prague, Czech Republic; Department of Immunology, 2nd Faculty of Medicine, Charles University, Motol University Hospital, V Úvalu 84, 150 06 Prague, Czech Republic.
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