Cervical neoplastic lesions are associated with infection by high-risk human papilloma viruses (HPVs). HPV-16 and HPV-18 are the most common genotypes. It has been proposed that development of HPV-16-positive cervical lesions is associated with impaired CD4+ T cell immunity against early Ags. The aim of the study was to evaluate whether this impairment also applies to HPV-18. We investigated the presence and the quality of anti-HPV-18 E6 CD4+ T cell responses in the blood of 37 consecutive patients with high-grade cervical lesions, 25 normal donors, and 20 cord bloods. The immune infiltrate in the cervical lesions was also evaluated. The characteristics of the responses were correlated to the clinical outcome. We found that one or more HPV-18 E6 peptides, containing naturally processed epitopes, were able to induce a response in 40–50% of the patients, depending on the effector function tested. Importantly, these percentages rose to 80–100% when HPV-18-positive patients were considered. HPV-18 E6-specific CD4+ T cells produced mixed Th1/Th2 responses and statistical analysis of the cytokines produced revealed that the amount of IFN-γ released could predict infection persistence and/or disease relapse after surgery. Finally, we found that a higher number of infiltrating CD4+ and T-bet+ T cells in the lesions correlated with a favorable clinical outcome. Our results strongly suggest a relevant role for CD4+ T cells in the control of the HPV-18 compared with HPV-16 infections in patients with high-grade cervical lesions and identify an immunologic parameter potentially useful for patients’ stratification.
Infection by 'high-risk' human papillomaviruses (HPV) is associated with the development of neoplastic lesions. HPV-18 is responsible for a very aggressive form of cancer and poor survival. As for other HPV types, immune surveillance has probably a role in the control of the infection. However, very little is known on HPV-18 immunogenicity. CD4 + T cells from 16 healthy donors were tested ex vivo for reactivity to synthetic peptides corresponding to 3 sequences on the HPV-18 E6 transforming protein predicted by bioinformatics as promiscuous HLA-DR ligands, and to the recombinant E6 protein. We found 3 donors with CD4 + T cells that specifically proliferated in the presence of HPV-18 E6 antigens and produced IFN-c in the presence of the E6 protein. We then propagated CD4 + T cell lines and clones from the responsive subjects to better characterize the recognized sequences. We show that E6 52-66 and E6 97-111 are indeed promiscuous and, most importantly, they contain naturally processed epitopes. Collectively, our data indicate that healthy donors may develop spontaneous CD4 immunity against HPV-18 E6 epitopes, thus strongly suggesting the potential for this protein to elicit in the host a natural productive immune response.
IntroductionCervical cancer is the second most common cancer in women worldwide and is associated with human papillomavirus (HPV) persistent infection. [1][2][3] In fact, HPV is detected in > 99% of cervical cancer and is now considered the primary aetiological agent in cervical cancer tumorigenesis.4 Development of HPV-related neoplastic lesions, from cervical intraepithelial neoplasia (CIN) to cervical carcinoma, is the result of infection by high-risk HPV, during which integration of the viral episome into the host-cell DNA frequently occurs. The two most common genotypes found in the lesions are HPV-16 and HPV-18, with a prevalence of 50-60% and 15-18%, respectively.
Purpose: Renal cell carcinoma (RCC) is considered immunogenic; nonetheless, rare tumorassociated antigens have been identified or are expressed in RCC. Peptidome (i.e., the total content of natural peptides of whole cells) from other tumors, such as melanoma, has proved to be immunogenic. The aims of this study were to determine whether peptidome from RCC is immunogenic and whether it contains tumor peptides shared among allogenic RCCs. Experimental Design: Autologous dendritic cells pulsed with RCC peptidome were used to activate in vitro CD4 + T cells from healthy donors and a metastatic RCC patient. CD4 + T-cell polyclonal lines and clones were characterized for tumor cell recognition by proliferation assay, killing activity, and cytokine secretion. Results: CD4 + T-cell lines and clones recognized HLA-DR-matched allogenic RCC and, for the patient, the autologous tumor. RCC-reactive CD4 + T cells showed a heterogeneous Th1 or Th0/Th2 pattern of cytokine secretion. Moreover, RCC-reactive CD4 + T cells recognized also melanoma, colon carcinoma, cervical carcinoma, pancreas carcinoma, lung carcinoma, gastric carcinoma, and lymphoma cells but not autologousT-cell blasts. Conclusions: Our results show that (a) the RCC peptidome contain antigens recognized by CD4 + Tcells and (b) shared among tumors of different histology and (c) it induces bothTh1-type and Th2/Th0-type immune responses. These data support the use of the peptidome from allogenic RCC for specific immunotherapy in RCC and possibly in other neoplastic diseases. Moreover, the CD4 + T-cell clones generated here are useful tools for tumor antigen identification.
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