Human Papillomavirus Type 16-Positive Cervical Cancer Is Associated with Impaired CD4+ T-Cell Immunity against Early Antigens E2 and E6

Abstract

Cervical cancer is the possible outcome of genital infection with highrisk human papillomavirus (HPV) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Fortunately, the majority of genital HPV infections are cleared before the development of (pre)malignant lesions. Analysis of CD4؉ T-helper (Th) immunity against the E2, E6, and E7 antigens of HPV16 in healthy women revealed strong proliferative E2-and E6-specific responses associated with prominent IFN-␥ and interleukin 5 secretion. This indicates that the naturally arising virus-induced immune response displays a mixed Th1/Th2 cytokine profile. Of all HPV16؉ cervical cancer patients, approximately half failed to mount a detectable immune response against the HPV16-derived peptides. The other half of the patients showed impaired HPV16-specific proliferative responses, which generally lacked both IFN-␥ and interleukin 5. This indicates that the HPV16-specific CD4؉ T-cell response in cervical cancer patients is either absent or severely impaired, despite a relatively good immune status of the patients, as indicated by intact responses against recall antigens. It is highly conceivable that proper CD4؉ T-cell help is important for launching an effective immune attack against HPV because infection of cervical epithelia by this virus is, at least initially, not accompanied by gross disturbance of this tissue and/or strong proinflammatory stimuli. Therefore, our observations concerning the lack of functional HPV16-specific CD4؉ T-cell immunity in patients with cervical cancer offer a possible explanation for the development of this disease.

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

“…The presence of HPV in the diluted samples was determined by genotyping the samples that demonstrated 65 basepair PCR amplimers on a 3% agarose gel using an INNOLiPA Genotyping Extra test (Innogenetics, Ghent, Belgium), according to the manufacturer's instruction. This assay allows the detection of the following HPV types: HPV 6,11,16,18,26,31,33,35,39,40,43,44,45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69/71, 73 and 74. Hybridization patterns were visually inspected and interpreted using a grid.…”

“…25, 26 The first and last amino acid within the sequence of the indicated antigen that is represented by the pooled peptides is indicated (e.g., E6 1-92). Memory response mix (MRM) was used as positive control.…”

“…Memory response mix (MRM) was used as positive control. 26,27 The capacity of T cells to proliferate on recognition of the antigen was determined by LST as described earlier. 27 The average of eight tested wells divided by the average of the medium control plus 3 SD was calculated and is referred to as the stimulation index (SI).…”

Rapid enrichment of human papillomavirus (HPV)‐specific polyclonal T cell populations for adoptive immunotherapy of cervical cancer

“…3 Advanced cervical cancer is associated with tumor-related immunosuppression, 4 the presence of increased numbers of regulatory T cells 5 and improperly polarized HPV-specific T cells. 6,7 Under these circumstances, active therapeutic vaccination will likely fail to establish effective immunity. An alternative approach is a passive therapeutic modality involving the adoptive transfer of tumor-specific T cells.…”

“…The allo-SCT can serve as a therapeutic platform to administer HPV16-specific T cells derived from the peripheral blood of the healthy stem-cell donor. The adoptive transfer of HPV16E6-specific Th1-type CD4 ϩ T cells, which are readily detected in the peripheral blood of the majority of healthy subjects, but are often lacking in HPV16-positive cervical cancer patients, 7,23 may contribute to the anti-tumor immunity. Tumor-specific CD4 ϩ Th1 type T cells have emerged as an essential component in anti-tumor immunity, fulfilling a multifactorial role, including the activation of antigen presenting cell (APC) maturation for efficient CD8 ϩ priming, the release of cytokines important in CD8 ϩ T cell proliferation and differentiation, and in the recruitment of other effector cells such as eosinophils and macrophages, capable of exerting anti-tumor reactivity.…”