Overlapping epitopes encompassing a point mutation (12 Gly → Arg) in p21 ras can be recognized by HLA‐DR, ‐DP and ‐DQ restricted T cells

Fossum, Beate; Gedde‐Dahl, Tobias; Hansen, Torbjern; Eriksen, Jon Amund; And, Erik Thorsby; Gaudernack, Gustav

doi:10.1002/eji.1830231045

Cited by 58 publications

(26 citation statements)

References 20 publications

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“…Important driver genes in colorectal 9,12 and pancreatic 13 tumorigenesis are mutated alleles of the oncogene KRAS and the tumor suppressor gene/oncogene TP53 . Indeed, mutated Kras and p53 proteins can comprise TSAs, as mutated Kras epitopes around the hot-spot mutation site G12 14-18 and also mutated p53 epitopes comprising hot-spot variants have previously been described. 19,20 …”

Section: Introductionmentioning

confidence: 98%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 98%

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

et al. 2018

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“…Such point mutations can be recognized both by helper T-cells (Th) and cytotoxic T-cells (CTL), as demonstrated in several studies by independent laboratories. [6][7][8] Mutant ras has therefore emerged as a bona fide tumor-specific antigen of particular interest in the treatment of pancreatic cancer. These observations led to the first peptide vaccine trial in humans, where patients with irresectable pancreatic cancer were treated with a personalized peptide vaccine corresponding to the K-ras mutations present in their tumor.…”

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confidence: 99%

Long‐term follow‐up of patients with resected pancreatic cancer following vaccination against mutant K‐ras

Wedén

Klemp

Gladhaug

et al. 2010

Intl Journal of Cancer

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165

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K‐ras mutations are frequently found in adenocarcinomas of the pancreas and can elicit mutation‐specific immune responses. Targeting the immune system against mutant Ras may thus influence the clinical course of the disease. Twenty‐three patients who were vaccinated after surgical resection for pancreatic adenocarcinoma (22 pancreaticoduodenectomies, one distal resection), in two previous Phase I/II clinical trials, were followed for more than 10 years with respect to long‐term immunological T‐cell reactivity and survival. The vaccine was composed of long synthetic mutant ras peptides designed mainly to elicit T‐helper responses. Seventeen of 20 evaluable patients (85%) responded immunologically to the vaccine. Median survival for all patients was 27.5 months and 28 months for immune responders. The 5‐year survival was 22% and 29%, respectively. Strikingly, 10‐year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of nonvaccinated patient treated in the same period. Three patients mounted a memory response up to 9 years after vaccination. The present observation of long‐term immune response together with 10‐year survival following surgical resection indicates that K‐ras vaccination may consolidate the effect of surgery and represent an adjuvant treatment option for the future.

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“…While this hypothesis is not contrary to the current immunological paradigm, very little is known about the function of DQ molecules; they are only constitutively present on a subfraction of antigen-presenting cells, and at a much lower density than DR molecules [13]. However, their expression on antigen-presenting cells can be induced by interferon 7 [14], and infectious agents such as the Epstein-Barr virus [15]. It has been postulated that DQ molecules exercise epistatic action over DR molecules [16] and that they are the mediators of immunosuppression [17].…”

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Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Routsias

Papadopoulos

1995

Diabetologia

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SummaryThe structural features of HLA-DQ alleles which are susceptible and resistant to insulin-dependent diabetes mellitus (IDDM) have been examined using a model of their three-dimensional structure obtained by energy minimisation, based on the published structure of HLA-DR1. The model shows DQ molecules to have an overall shape nearly identical to that of DR molecules, but with significant differences in the fine structure: 1) the antigen-binding groove of DQ molecules has a polymorphic first pocket; this pocket can be either amphiphilic or hydrophilic, 2) The [349-56 dimerisation domain of DQ is polymorphic: hydrophobic, or amphiphilic, or hydrophilic and positively charged, leading to spontaneous or T-cell receptor-induced homodimer formation, or difficulty of the formation of such dimers, respectively; 3) a prominent Arg-Gly-Asp loop is formed by some DQ alleles ([3167-169) and probably functions in cell adhesion. There are also small differences in the residues and sequences implicated in CD4 binding but the significance of these differences cannot be evaluated at present. All seven DQ alleles which confer susceptibility to IDDM posses a hydrophilic first pocket in the antigen-binding groove, a hydrophobic or amphiphilic [349-56 dimerisation patch that allows for spontaneous or T-cell receptor-induced dimerisation, and the Arg-Gly-Asp loop. By contrast, in the protective alleles at least one of these three features is absent. This segregation of phenotypes according to susceptibility or resistance can well explain the model of tighter autoantigen binding by the protective alleles compared to the susceptible alleles, previously proposed for the pathogenesis of IDDM. [Diabetologia (1995[Diabetologia ( ) 38: 1251[Diabetologia ( -1261

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Overlapping epitopes encompassing a point mutation (12 Gly → Arg) in p21 ras can be recognized by HLA‐DR, ‐DP and ‐DQ restricted T cells

Cited by 58 publications

References 20 publications

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

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

Long‐term follow‐up of patients with resected pancreatic cancer following vaccination against mutant K‐ras

Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

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