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

Abstract

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...

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…Circulating T cells reacting against HPV16 E6 or E7 peptides were detected in the blood, often in patients with an HPV16þ tumor, largely extending previous data on HLA-A2 restricted T cells in a small group of patients 7 Similar to what was observed in patients with cervical carcinoma the HPV16-specific T-cell proliferative responses in HNSCC were not/hardly ever accompanied by the production of IFNc. 26,32 Although these responses in the blood clearly show that adaptive immune responses are induced upon exposure to the HPV viral oncoproteins, this reaction does not necessarily reflect an ongoing immune response against the tumor. This is exemplified by the detection of circulating HPV16-specific T cells in the blood of some patients with HPV-negative tumors, which in a number of cases displayed a similar cytokine profile as described for HPV16-specific reactivity in healthy females.…”

Protein vaccination with HPV16 E7/Pep‐1 nanoparticles elicits a protective T‐helper cell‐mediated immune response

“…The most common high-risk types are the HPV-16 and HPV-18, respectively, associated with pre-cancers and cancers in various anogenital sites (e.g., cervix, vulva, vagina, and anus) (3)(4)(5)(6). The studies showed that HPV-specific T-cell responses induced by vaccines play an effective role in tumor regression (7)(8)(9)(10). The researchers indicated that therapeutic HPV vaccines have the potential to inhibit the tumor growth by targeting HPV oncoproteins (11).…”

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

“…A recent study has revealed that cervical extracts, in particular the protease component, can suppress lympho-proliferative responses [71], whereas expression of FasL on cervical tumors can cause apoptosis of the infiltrating lymphocytes [72]. These results also indicate that the production of regulatory T cells may be an important suppressive mechanism in cervical cancer [73,74], because regulatory T cells suppress the induction of type 1-helper T (Th1) cells [75], and IFN--producing Th cells are required to mobilize CD8 + T cells to the site of HPV infection [76]. Therefore, a successful immunotherapeutic approach to cervical cancer must circumvent the activity of these cells types and other local immunosuppressive mechanisms.…”