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

• Published in: Oncoimmunology Vol. 7; no. 12; p. e1500671
• Main Authors: Quandt, Jasmin, Schlude, Christoph, Bartoschek, Michael, Will, Rainer, Cid-Arregui, Angel, Schölch, Sebastian, Reissfelder, Christoph, Weitz, Jürgen, Schneider, Martin, Wiemann, Stefan, Momburg, Frank, Beckhove, Philipp
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.12.2018; Taylor & Francis Group
• Subjects: Basic Medicine; common driver mutations; Immunologi inom det medicinska området; Immunology in the medical area; Kras; Long-peptide vaccination; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Original Research; p53; reg; regulatory T cells; treg; tumor mutation specific T cell responses; tumor-specific mutated antigens; regulatory T cells; tumor mutation specific T cell responses; Treg; common driver mutations; Kras; Long-peptide vaccination; tumor-specific mutated antigens; p53
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2018.1500671

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.