Systemic T-cell and humoral responses against cancer testis antigens in hepatocellular carcinoma patients

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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+ and CD8+ T-cell responses against these CTAs were found in 14/16 analyzed HCC patients. CTA-peptide stimulation-induced granzyme B, IL2, and TNFa in 8/8 analyzed patients, including two MAGEA1 peptides included based on in silico prediction. Finally, IgG responses were observed in 13/32 patients, albeit with low titers. The presence of CD4+ and CD8+ T-cells and IgG responses shows the immunogenicity of these CTAs in HCC-patients. We hypothesize that vaccines based on these tumor-specific antigens may boost preexisting CTA-specific immunity and could enhance therapeutic efficacy of ICPI in advanced HCC.

Original languageEnglish
Article number2131096
JournalOncoImmunology
Volume11
Issue number1
DOIs
Publication statusPublished - 8 May 2022

Bibliographical note

Funding Information:
This study was supported by the Erasmus MC PhD grant 2014 awarded to dr. J. Kwekkeboom by the Erasmus Medical Center, Rotterdam. We would like to thank Dr. Hanneke van Vuuren (Department of Gastroenterology and Hepatology, Erasmus MC, for providing us with frozen plasma samples of healthy blood bank donors. Finally, we would like to thank Prof. Dr. Stefan Eichmüller from the department of GMP & T-cell therapy of the Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany, for providing us with positive control sera for the CTA-specific IgG ELISAs.

Publisher Copyright:
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

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