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000142110 1001_ $$0P:(DE-HGF)0$$aQuandt, Jasmin$$b0$$eFirst author
000142110 245__ $$aLong-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses.
000142110 260__ $$aAbingdon$$bTaylor & Franics$$c2018
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000142110 520__ $$aMutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28-35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.
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000142110 7001_ $$0P:(DE-HGF)0$$aSchlude, Christoph$$b1
000142110 7001_ $$00000-0002-1567-795X$$aBartoschek, Michael$$b2
000142110 7001_ $$0P:(DE-He78)18218139eec55d83cf82679934e5cd75$$aWill, Rainer$$b3$$udkfz
000142110 7001_ $$0P:(DE-He78)a30064f6b2d9ab959d35315d7668c091$$aCid-Arregui, Angel$$b4$$udkfz
000142110 7001_ $$00000-0003-0012-3177$$aSchölch, Sebastian$$b5
000142110 7001_ $$aReissfelder, Christoph$$b6
000142110 7001_ $$aWeitz, Jürgen$$b7
000142110 7001_ $$aSchneider, Martin$$b8
000142110 7001_ $$0P:(DE-He78)f6bebe05e7a748d3cbf9f59659567d52$$aWiemann, Stefan$$b9$$udkfz
000142110 7001_ $$0P:(DE-He78)b2290261145f21c46f2d42783c69d104$$aMomburg, Frank$$b10$$udkfz
000142110 7001_ $$0P:(DE-He78)1732377f6242a18280bc6aaa196988d1$$aBeckhove, Philipp$$b11$$eLast author$$udkfz
000142110 773__ $$0PERI:(DE-600)2645309-5$$a10.1080/2162402X.2018.1500671$$gVol. 7, no. 12, p. e1500671 -$$n12$$pe1500671 -$$tOncoImmunology$$v7$$x2162-402X$$y2018
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