CD4+ T cell responses to HLA-DP5-restricted wild-type sequence p53 peptides in patients with head and neck cancer

Abstract

Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines. Evidence has been accumulating which indicates that CD4+ Th cells have an important role in generating and maintaining antitumor immune responses. To elucidate the nature of CD4+ Th responses to wt p53 epitopes in patients with squamous cell carcinoma of the head and neck (SCCHN), peripheral blood mononuclear cells (PBMCs) from HLA-DP5+ patients were stimulated with HLA-DP5-restricted wt p53 peptides, p53108–122 or p53153–166, and tested for the release of IFN-γ and IL-5 in ELISPOT assays. Immunohistochemistry for p53 accumulation in tumors, and ELISA for serum antibodies to p53 were also performed. Eleven (57.9%) of 19 HLA-DP5+ patients but none of 5 healthy donors had detectable Th1 and/or Th2 responses to wt p53 peptides by ELISPOT assay. Among these 11 responding patients, 9 (81.8%) and all 11 (100%) patients had a tumor burden and p53 accumulation, respectively. On the other hand, two responding patients were in post-operative condition. Interestingly, among nine patients with a tumor burden, four patients with early disease showed either Th1-polarized or mixed Th1/Th2 responses, while five patients with advanced disease showed either Th2-polarized or mixed Th1/Th2 responses. Our results suggest that wt p53108–122 and p53153–166 peptides stimulate both Th1- and Th2-type CD4+ T cell responses in patients with SCCHN, and anti-p53 Th responses may persist even after surgical resection of the tumor; however, the presence of a tumor and its progression may affect the nature of immune responses to wt p53 peptides.

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

“…As in many other cancer types, 17 a progressive increase in Th2 response has been described in HNSCC; [18][19][20] nevertheless, the shift toward Th2 cells seems incomplete. Indeed, a concomitant increase of both Th1 and Th2 cells with a minimal variation of Th1 over Th2 cells ratio has been often reported in HNSCC.…”

“…Indeed, a concomitant increase of both Th1 and Th2 cells with a minimal variation of Th1 over Th2 cells ratio has been often reported in HNSCC. 18,21 Similarly, a shift toward Th2-related cytokines, with an increase of IL-4, IL-10 and TGFb, and a subsequent decrease of the most important Th1 mediator, INFg, is often observed in HNSCC. 9,[22][23][24][25][26][27][28] The increase of IL-10, known as one of the strongest immune suppressive factors, is correlated with tumor staging, nodal involvement and to a worst prognostic factor.…”

Intratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cells

“…The inclusion of an experimental neoantigen was dictated by multiple reports showing that tumors naturally produce antigenic epitopes derived from mutant as well as native proteins. These antigenic epitopes are able to elicit activation, clonal expansion and acquisition of effector functions by antigen specific cytotoxic and helper CD4 + T cells [47] – [51] . In conclusion, by using tumor cells expressing a neoantigen, we facilitate studies how cellular mechanisms are established that protect tumors from the immune system and result in the induction of an active tolerance/anergy mediated by T reg cells [14] , [52] .…”

High immunogenic potential of p53 mRNA-transfected dendritic cells in patients with primary breast cancer

“…Data from a few selected patients suggest a favorable clinical course in patients with pre-existent TAA-directed immunity [18,19]. In this regard, pre-existing T-cell responses to p53 have been reported in cancer patients [20][21][22]. However, results have been conflicting with regard to the prevalence of preexisting TAA-directed T-cell responses in breast cancer [9][10][11]23].…”