Interferon gamma (IFNγ) is a key moderator of cell-mediated immunity with diverse, mainly pro-inflammatory actions on immunocytes and target tissue. Recent studies have shown it may enhance ...anti-tumor and antiviral effects of CD8 T cells. Here we investigate the mechanisms by which IFNγ mediates CD8 T-cell cytotoxic function. We show that in vivo, antigen-specific CD8 T cells that produce INFγ are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFNγ enhanced their ability to migrate to the site of antigen-presenting skin cells. By in vivo imaging, we show that CTL motility, particularly speed, during graft rejection was enhanced by locally available IFNγ. We then used a reductionist two-cell model of CTL effectors and keratinocyte targets to investigate the effects of locally available (paracrine) and CTL-producing (autocrine) IFNγ on the motility behavior and killing ability of the CTL. Using live-cell imaging by prolonged time-lapse microscopy of primary effector CD8 T cells and antigen-expressing primary keratinocyte targets, we show that CD8 T-cell cytotoxic function and motility is enhanced by locally available IFNγ. Conversely, deprivation of either autocrine or paracrine IFNγ, or blockade of IFNγ signaling to CTL markedly reduced their cytotoxic function, their kinematics, and effector cell survival. We conclude that in vitro and in vivo, autocrine production of IFNγ by CTL enhances their motility and promotes killing of primary target keratinocytes. The absolute need for local IFNγ to enable cytotoxic CD8 T-cell function is of significance for immunotherapy for chronic viral infection and for cancer.
Human papillomaviruses are causally associated with 5% of human cancers. The recent discovery of a papillomavirus (MmuPV1) that infects laboratory mice provides unique opportunities to study the life ...cycle and pathogenesis of papillomaviruses in the context of a genetically manipulatable host organism. To date, MmuPV1-induced disease has been found largely to be restricted to severely immunodeficient strains of mice. In this study, we report that ultraviolet radiation (UVR), specifically UVB spectra, causes wild-type strains of mice to become highly susceptible to MmuPV1-induced disease. MmuPV1-infected mice treated with UVB develop warts that progress to squamous cell carcinoma. Our studies further indicate that UVB induces systemic immunosuppression in mice that correlates with susceptibility to MmuPV1-associated disease. These findings provide new insight into how MmuPV1 can be used to study the life cycle of papillomaviruses and their role in carcinogenesis, the role of host immunity in controlling papillomavirus-associated pathogenesis, and a basis for understanding in part the role of UVR in promoting HPV infection in humans.
Abstract Human papillomavirus (HPV) infections are generally long lasting, and a host immune response to infection is hard to detect. Nevertheless immunocompromised subjects control HPV infection ...less well than those with intact immunity. Immune responses are best documented for the papillomavirus groups that cause evident human disease, particularly those responsible for anogenital cancers and genital warts. Humoral immunity to the viral capsid has been shown sufficient for protection against infection, while innate and adaptive cell mediated immunity appears important for eventual elimination of HPV infection. However, molecular and cellular mechanisms responsible for protection from and clearance of HPV infection are not completely established.
Translation of basic scientific findings into practical patient outcomes is a significant exercise even when the goal is conceptually straightforward, as in the development of a vaccine for an ...infectious disease. Recognition of the association of cervical cancer with papillomavirus infection encouraged development of a vaccine to help with prevention of this very common cancer, causing over 250,000 deaths each year worldwide. To introduce a vaccine program, it was however necessary to develop a technology for making viral Ag, demonstrate that systemic immunization could provide mucosal surface protection in the genital tract, develop assays for vaccine potency, and understand enough about the epidemiology and natural history of the infection to plan effective intervention strategies. This process took ∼25 years. The major hurdle, now that effective vaccines are available, is to ensure their deployment in the countries where they are most needed. The development and deployment of human papillomavirus vaccines demonstrate the benefits of collaborative research activity across the globe, and between academia and industry, to translate scientific discoveries into public health benefits.
A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci ...involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.
A subset of human papillomaviruses (HPVs) promote anogenital malignancy, including cervical cancer, and prevention and treatment strategies that reflect the causal role of HPV are being developed. ...Vaccines based on HPV virus-like particles induce genotype-specific virus-neutralizing antibody and prevent infection with HPV. Persistent papillomavirus infection is required for the development of papillomavirus-associated cancer and, therefore, therapeutic vaccines are being developed to eliminate established papillomavirus infection. Such vaccines test principles for the growing field of tumour-antigen-specific immunotherapy. This article reviews progress in the field and draws conclusions for the development of future prophylactic and therapeutic viral vaccines.
A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to ...reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.
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•A strategy for improving the ADCC potential of therapeutic antibodies is presented•Temporary inhibition of endocytosis increases tumor cell antigen presentation•Prochlorperazine could be repurposed to enhance the efficacy of anti-tumor mAbs•Potential to reduce heterogeneity in tumor cell responses to many IgG1 antibodies
Endocytosis inhibitors, such as prochlorperazine, can be used to move tumor cell antigens that are the targets of therapeutic monoclonal antibodies but hiding inside the cell to the cell surface for improved therapeutic antibody binding and tumor cell destruction by NK cells.
Human papillomavirus (HPV) related tumours account for a significant proportion of head and neck squamous cell carcinomas (HNSCCs) in developed countries. They respond better to chemo- and ...radio-therapy, and have a better stage specific prognosis. To establish their prevalence in China, we assessed a series of histology confirmed HNSCCs collected in Zhejiang and Guangdong provinces by PCR for HPV DNA and by immunohistochemistry for p16 protein status. Among 303 HNSCCs, HPV DNA was detected in 26.4%, with HPV16 DNA in 71% of these. Of HNSCC located in the oropharynx, 38.55% (32/83) were HPV+ve. In this series, p16 status was a relatively poor predictor of HPV status as detected by PCR. The stage specific survival time of HPV+ HNSCCs was significantly longer than for HPV- HNSCC. HPV status should be assessed for oropharyngeal cancers in China to assist with appropriate management, and prophylaxis against HPV infection should be considered to reduce the incidence of this disease.
In 2007, Australia was one of the first countries to introduce a national human papillomavirus (HPV) vaccination programme, and it has since achieved high vaccination coverage across both sexes. In ...December, 2017, organised cervical screening in Australia transitioned from cytology-based screening every 2 years for women aged from 18–20 years to 69 years, to primary HPV testing every 5 years for women aged 25–69 years and exit testing for women aged 70–74 years. We aimed to identify the earliest years in which the annual age-standardised incidence of cervical cancer in Australia (which is currently seven cases per 100 000 women) could decrease below two annual thresholds that could be considered to be potential elimination thresholds: a rare cancer threshold (six new cases per 100 000 women) or a lower threshold (four new cases per 100 000 women), since Australia is likely to be one of the first countries to reach these benchmarks.
In this modelling study, we used Policy1-Cervix—an extensively validated dynamic model of HPV vaccination, natural history, and cervical screening—to estimate the age-standardised incidence of cervical cancer in Australia from 2015 to 2100. We incorporated age-specific coverage of the Australian National HPV Vaccination Program in girls, including the catch-up programme, and the inclusion of boys into the vaccine programme from 2013, and a change from the quadrivalent to the nonavalent vaccine from 2018. We also modelled the effects of the transition to primary HPV screening. We considered two scenarios for future screening recommendations regarding the cohorts who will be and who have been offered the nonavalent vaccine: either that HPV screening every 5 years continues, or that no screening would be offered to these women.
We estimate that, in Australia, the age-standardised annual incidence of cervical cancer will decrease to fewer than six new cases per 100 000 women by 2020 (range 2018–22), and to fewer than four new cases per 100 000 women by 2028 (2021–35). The precise year of attaining these rates is dependent on the population used for age-standardisation, HPV screening behaviour and test characteristics, the incremental effects of vaccination of men on herd immunity in women, and assumptions about the future frequency of benign hysterectomies. By 2066 (2054–77), the annual incidence of cervical cancer will decrease and remain at fewer than one case per 100 000 women if screening for HPV every 5 years continues for cohorts who have been offered the nonavalent vaccine, or fewer than three cases per 100 000 women if these cohorts are not screened. Cervical cancer mortality is estimated to decrease to less than an age-standardised annual rate of one death per 100 000 women by 2034 (2025–47), even if future screening is only offered to older cohorts that were not offered the nonavalent vaccine.
If high-coverage vaccination and screening is maintained, at an elimination threshold of four new cases per 100 000 women annually, cervical cancer could be considered to be eliminated as a public health problem in Australia within the next 20 years. However, screening and vaccination initiatives would need to be maintained thereafter to maintain very low cervical cancer incidence and mortality rates.
National Health and Medical Research Council (Australia).
Antigen presenting cells (APCs) in skin can promote either antigen-specific effector functions or antigen tolerance, and thus determine clearance or persistence of cutaneous viral infections. Human ...papillomavirus (HPV) infections can persist in squamous epithelium in immunocompetent individuals, and some persisting HPV infections, particularly with HPV16, promote malignant epithelial transformation. Here, we investigate whether local expression of the HPV16 protein most associated with malignant transformation, HPV16-E7, affects the phenotype and function of APC subsets in the skin. We demonstrate an expanded population of Langerhans cells in HPV16-E7 transgenic skin with distinct cell surface markers which express immune-modulatory enzymes and cytokines not expressed by cells from non transgenic skin. Furthermore, HPV16-E7 transgene expression in keratinocytes attracts new APC subsets to the epidermis. In vivo migration and transport of antigen to the draining lymph node by these APCs is markedly enhanced in HPV16-E7 expressing skin, whereas antigen-processing, as measured by proteolytic cleavage of DQ-OVA and activation of T cells in vivo by APCs, is significantly impaired. These data suggest that local expression of HPV16-E7 in keratinocytes can contribute to persisting infection with this oncogenic virus, by altering the phenotype and function of local APCs.
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