Increase of human papillomavirus‐16 E7‐specific T helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy

Delgado, G.; Martínez, Elizabeth Lorenzo; Cespedes, Maria A.; Bravo, María Mercedes; Navas, María Cristina; Rojas, Alba Lucía Cómbita

doi:10.1111/j.1365-2567.2008.02912.x

Cited by 17 publications

(12 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HPV‐specific immunity, in patients who showed an HPV‐specific proliferative response, consisted of circulating FoxP3‐negative and ‐positive CD4+C25+ T cells. This large study confirms previous findings in small groups of patients 5, 32–34. Moreover, it allows a more definitive conclusion with respect to the response rate and the type of the T‐cell response to the tumor‐specific HPV E6 and E7 antigens in patients with CxCa as well as scrutiny of the relationship between HPV‐specific immunity and tumor characteristics or survival.…”

Section: Discussionsupporting

confidence: 88%

The detection of circulating human papillomavirus‐specific T cells is associated with improved survival of patients with deeply infiltrating tumors

Heusinkveld

Welters

Poelgeest

et al. 2010

Intl Journal of Cancer

View full text Add to dashboard Cite

A detailed analyses of HPV-specific immunity was performed in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors. Patients were HLA-typed and HPV16/18-specific T-cell immunity was assessed by proliferation assay and cytometric bead array using freshly isolated PBMC and by phenotypic analysis of HPVspecific T cells. The results were analyzed in relation to known disease-related HLA-types (DR7, DR13, DR15/DQ06), invasiondepth and size of tumor, lymph node (LN) status and disease free survival. In total 119 HLA-typed patients with CxCa were analyzed. Patients expressing the HLA-DR13 haplotype were underrepresented as compared to the Dutch population (p 5 0.014), whereas HLA-DR7 was overrepresented in patients with HPV161 CxCa (p 5 0.006). In 29 of 94 patients (31%) from whom blood could be tested, a proliferative response to HPV16/18 was detected, which was associated with increased numbers of HPV-specific CD41CD251 (activated) T cells (p 5 0.03) and HPV-specific CD41CD251FoxP3-positive T cells (p 5 0.04). The presence of both FoxP3-positive and negative HPV-specific CD41CD251 T cells was significantly correlated (p 5 0.01). Interestingly, the detection of HPV-specific proliferation was associated with invasion depth (p 5 0.020) but not with HLA type, tumor size nor LN status. Moreover, the detection of HPV-specific immunity was associated with an improved disease free survival (p 5 0.04) in patients with deeply infiltrating tumors. In conclusion, HPV-specific proliferative T-cell response, comprising higher percentages of HPV-specific CD251 and CD251FoxP3-positive CD41T cells, are more frequently detected in patients with deep infiltrating CxCa tumors and associated with an improved survival.Cervical cancer (CxCa) is the second most common cancer in women worldwide. 1 It develops as a result of an uncontrolled, persistent infection with a high-risk type of human papillomavirus (HPV), in particular types HPV16 and HPV18. 2 The HPV genome encodes two oncoproteins, E6 and E7, which are constitutively expressed in high-grade cervical lesions and cancer since they are required for the onset and maintenance of the malignant cellular phenotype. 3 As the HPV proteins are foreign to the body one would expect the immune system to respond against these antigens when expressed in the cervical epithelium. Indeed, HPV16-specific Th1-and Th2-type CD4þ proliferative T-cell responses were frequently detected in PBMC cultures of healthy individuals 4-6 and both HPV16-specific CD4þ and CD8þ T cells are able to migrate upon antigenic challenge in exposed healthy individuals 7 showing that successful defense against HPV16 infection is commonly associated with the induction of a systemic effector T-cell response against these viral antigens. This notion is sustained by our most recent study showing that the full regression of HPV16-induced high-grade vulvar lesions is strongly associated with the strength of vaccine-induced HPV-specific immunity against these early antigens...

show abstract

Section: Discussionsupporting

confidence: 88%

The detection of circulating human papillomavirus‐specific T cells is associated with improved survival of patients with deeply infiltrating tumors

Heusinkveld

Welters

Poelgeest

et al. 2010

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Such a beneficial role for (chemo)radiation in host immune response to HPVOPC would be consistent with recent clinical literature describing immune-stimulating effects of chemotherapy and radiation in melanoma (25,26) and esophageal squamous cell carcinoma (27). However, the results of clinical studies in HPV+ cervical and oropharyngeal cancers have been mixed, with some studies showing evidence of post-treatment immune activation (28,29) and others immune suppression (30–32). It is possible that different treatment regimens may have differing effects on anti-tumor immunity, as has been shown in at least one study which found an immune-enhancing effect in the draining nodes after low-dose XRT but an immunosuppressive effect of high-dose XRT (50 Gy – consistent with standard-of-care clinical practice (32).…”

Section: Discussionmentioning

confidence: 99%

Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

et al. 2014

View full text Add to dashboard Cite

While viral antigens in HPV-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from stage III–IV OPC patients undergoing concomitant chemoradiotherapy (CRT) with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T cell assays in the presence of blocking antibody. While HPV-specific T cell responses were present in 13/18 patients prior to treatment, 10/13 patients lost these responses within 3 months after CRT. CRT decreased circulating T cells and markedly elevated MDSC. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after CRT, and ex-vivo culture with PD-1 blocking antibody enhanced HPV-specific T cell responses in 8/18 samples tested. CRT suppresses circulating immune responses in HPVOPC patients by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care CRT for HPVOPC.

show abstract

“…However, an increase of HPV-16 E7-specific T-helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy is not enough for controlling tumor cell regression [40] . This observation underlines the importance of several mechanisms that could influence the anti-tumoral immune response.…”

Section: Discussionmentioning

confidence: 99%

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Rodríguez¹,

Galeano²,

Palacios

et al. 2011

Pathobiology

Self Cite

View full text Add to dashboard Cite

Although high-risk human papillomaviruses (HPVs) are an important risk factor in the etiopathogenesis of cervical cancer, increasing evidence suggests that the ability to avoid immune surveillance seems to be linked to the transforming potential of HPV and a rapid progression to cancer. In other cancer models, IL-10 contributes to impair anti-tumor immune response either by downregulating human leukocyte antigen Class I (HLA-I) expression or by increasing HLA-G expression. To comprehend how these alterations could contribute to evasion of immune surveillance in cervical cancer, we analyzed HLA-I, HLA-G and IL-10 expressions by immunohistochemistry in 63 biopsies from patients with cervical intraepithelial neoplasia III (CIN-III) and cervical cancer. Immunohistochemistry showed absent or weak HLA-I expression in 50/59 cases. In these cases, a high percentage had loss of heterozygosis. IL-10 and HLA-G expression were observed in 46.6 and 27.6% of cases, respectively. Concurrent upregulation of IL-10 was found in 87.5% of HLA-G positive cases (p = 0.000). Similarly, a significant association between IL-10 expression and HLA-I downregulation was found (p = 0.028). Finally, we observed higher HLA-G expression in patients with HLA-I downregulation than in those with normal HLA-I expression (p = 0.004). Our results suggest that, in cervical cancer, the IL-10 expression may induce an immunosuppressive environment by upregulating HLA-G expression and downregulating HLA class I expression.

show abstract

Increase of human papillomavirus‐16 E7‐specific T helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy

Cited by 17 publications

References 30 publications

The detection of circulating human papillomavirus‐specific T cells is associated with improved survival of patients with deeply infiltrating tumors

The detection of circulating human papillomavirus‐specific T cells is associated with improved survival of patients with deeply infiltrating tumors

Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Contact Info

Product

Resources

About