Quandt, Jasmin and Schlude, Christoph and Bartoschek, Michael and Will, Rainer and Cid-Arregui, Angel and Schoelch, Sebastian and Reissfelder, Christoph and Weitz, Juergen and Schneider, Martin and Wiemann, Stefan and Momburg, Frank and Beckhove, Philipp (2018) Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses. ONCOIMMUNOLOGY, 7 (12): e1500671. ISSN 2162-402X,
Full text not available from this repository. (Request a copy)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 T(H)1-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 (T-reg) 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 T(reg)s.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BONE-MARROW; TUMOR-ANTIGEN; OVERLAPPING EPITOPES; COLORECTAL-CANCER; IMMUNE-RESPONSE; HLA-DP; RAS; VACCINES; LYMPHOCYTES; CD4(+); Long-peptide vaccination; tumor-specific mutated antigens; tumor mutation specific T cell responses; regulatory T cells; T-reg; common driver mutations; p53; Kras |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 08:09 |
| Last Modified: | 04 Oct 2019 08:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13381 |
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