CD4⁺ T cells against human papillomavirus‐18 E7 in patients with high‐grade cervical lesions associate with the absence of the virus in the cervix

Abstract

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.

Human papilloma virus status of penile squamous cell carcinoma is associated with differences in tumour-infiltrating T lymphocytes

“…In this regard, the presence of tumour-infiltrating lymphocytes, specific for HPV 16 in the majority of HPV-positive SCCs of the head and neck, provides evidence in favour of a specific T cell reaction to HPV antigens in HPV type 16 associated SCC [34]. In addition, high numbers of HPV-specific T cells in peripheral blood have been described in several studies of head and neck SCC [35,36], vulvar intraepithelial neoplasia [37] and cervical intraepithelial neoplasia lesions [38][39][40]. Functional data showed that HPV-specific T cells are able to mount a response against HPV-positive cancer cells [35,41].…”

“…The LCD-array HPV 3.5C uses primer pairs and capture probes specific for HPV types 06, 11, 16, 18, 31, 33, 35, 39, 42, 44, 45, Tumours negative for HPV were examined a second time using a multiplex HPV genotyping assay. GP5+/GP6+ primer-based multiplex PCR and genotyping were performed using Luminex-based multiplexed genotyping (MPG, multiplexed HPV genotyping, Multimetrix, Heidelberg, Germany) for detection of 18 high-risk HPV genotypes (HPV 16,18,26,31,33,35,39,45,51, 52, 53, 56, 58, 59, 66, 68, 73 and 82) and 6 low-risk HPV genotypes (HPV 6, 11, 42, 43, 44 and 70) [13,14] Quantification of lymphocytes The number of labelled lymphocytes was counted for each case in five different representative high-power fields (HPFs) (×40 objective; 22-mm field of view ocular) of tumour tissue and adjacent stroma using an Olympus BX40 microscope (Olympus Europe Holding GmbH, Hamburg, Germany), blinded to the HPV status of tumours.…”

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer

“…The expansion of HPV16-specific CD4+ T cell was found in all nine patients tested in detail, and in three patients, also HPV16-specific CD8+ T cells were detected. The bias toward CD4+ T cell reactivity against HPV-derived epitopes is not likely a result of the culture method used here, but more a reflection of what is generally found in the spontaneous T cell response to HPV in cervical cancer [17, 18, 29–31], as well as among TILs from patients with head and neck cancer [32]. The T helper type 1 (Th1) cytokine IFNγ was produced in all LNMC cultures and in some cases also the Th2 cytokines IL-10 and IL-5.…”

Mucosal Immunity in the Female Genital Tract, HIV/AIDS

“…The virus infects basal epithelial cells through microabrasions on the epithelial surface. The oncogenesis depends on the integration of the viral episome into the DNA of the epithelial cell [ 300 ] and on the activity of the viral oncoproteins E6 and E7 [ 301 ]. Both CD4 + and CD8 + T-cells are capable of recognizing these proteins.…”

“…The development of HPV-16 associated lesions, the most common high risk HPV subtype and that has early progression [ 302 ], is connected with the ineffective immune response against HPV-16 E6 and E7 [ 310 ]. The immune status also appears to influence the prevalence of HPV-18, which is between 15% and 18% in immunocompetent women and approximately 80% in immunocompromised women [ 300 ].…”