TY  - JOUR
AU  - Quandt, Jasmin
AU  - Schlude, Christoph
AU  - Bartoschek, Michael
AU  - Will, Rainer
AU  - Cid-Arregui, Angel
AU  - Schölch, Sebastian
AU  - Reissfelder, Christoph
AU  - Weitz, Jürgen
AU  - Schneider, Martin
AU  - Wiemann, Stefan
AU  - Momburg, Frank
AU  - Beckhove, Philipp
TI  - Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses.
JO  - OncoImmunology
VL  - 7
IS  - 12
SN  - 2162-402X
CY  - Abingdon
PB  - Taylor & Franics
M1  - DKFZ-2018-02340
SP  - e1500671 -
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30524892
C2  - pmc:PMC6279329
DO  - DOI:10.1080/2162402X.2018.1500671
UR  - https://inrepo02.dkfz.de/record/142110
ER  -