Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

• Verfasst von: Quandt, Jasmin [VerfasserIn]
• Verfasst von: Cid Arregui, Angel [VerfasserIn]
• Verfasst von: Schölch, Sebastian [VerfasserIn]
• Verfasst von: Reißfelder, Christoph [VerfasserIn]
• Verfasst von: Schneider, Martin [VerfasserIn]
• Verfasst von: Wiemann, Stefan [VerfasserIn]
• Verfasst von: Momburg, Frank [VerfasserIn]
• Verfasst von: Beckhove, Philipp [VerfasserIn]
• Titel: Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses
• Verf.angabe: Jasmin Quandt, Christoph Schlude, Michael Bartoschek, Rainer Will, Angel Cid-Arregui, Sebastian Schölch, Christoph Reissfelder, Jürgen Weitz, Martin Schneider, Stefan Wiemann, Frank Momburg, and Philipp Beckhove
• E-Jahr: 2018
• Jahr: 21 Sep 2018
• Umfang: 21 S.
• Fussnoten: Gesehen am 18.05.2020
• Titel Quelle: Enthalten in: OncoImmunology
• Ort Quelle: Abingdon : Taylor & Franics, 2012
• Jahr Quelle: 2018
• Band/Heft Quelle: 7(2018,12) Artikel-Numemr e1500671, 21 Seiten
• ISSN Quelle: 2162-402X
• DOI: doi:10.1080/2162402X.2018.1500671
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: common driver mutations
• Sach-SW: Kras
• Sach-SW: Long-peptide vaccination
• Sach-SW: p53
• Sach-SW: regulatory T cells
• Sach-SW: Treg
• Sach-SW: tumor mutation specific T cell responses
• Sach-SW: tumor-specific mutated antigens
• K10plus-PPN: 1698493762

Abstract

Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28-35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.