Human papillomavirus (HPV) associated tumors of the anogenital epithelium, and the corresponding HPV associated premalignant lesions, occur more frequently in immunodeficient and immunosuppressed patients than in otherwise matched control subjects. Reflective of this, the CDC has now identified cervical cancer, a malignancy associated in most cases with HPV infection, as a prognosticator of AIDS in HIV infected patients. In this application we address the role of immune surveillance in the control of the development of HPV associated tumors. This proposal makes use of a series of transgenic animal models which mimic the multistep oncogenic process associated with HPV infection. As with HPV associated tumors in man, tumors arising in these transgenic mice a) arise in vivo from a premalignant precursor, b) are induced by the E6 and E7 proteins of HPV, c) express E7 protein as a tumor specific antigen ,and d) are squamous cell carcinomas, similar to the majority of cervical cancers associated with HPV infection. This model avoids using transplantable tumors, which are not subjected to immune selection pressure, and allows observation of the effect of controlled CD4 depletion, and other immune suppression, on the evolution of the tumor. Using this animal model, our proposed studies will test hypotheses concerning a) mechanisms of tumor immune surveillance b) the role of CD4 +ve T cell depletion and other immune disturbances associated with HIV infection in tumor initiation and progression, and c)the possibility of immune intervention in HIV infected and other subjects with HPV associated tumors.
The specific aims are as follows:
Aim 1. Establish, in the line 19 transgenic mouse, how an immune response to HPV16E7, a tumor specific antigen(TSA), can prevent and/or eliminate HPV16E7 expressing tumors Aim 1.1 Establish the role of different types of cell mediated immunity in rejection of E7 expressing tumors Aim 1.2 Assess whether immunization with HPV16E7 can enhance rejection of skin expressing HPV16E7.
Aim 1. 3 Assess whether immunization with HPV1 6 E7 can prevent development of HPV16E7+ve epithelial tumors.
Aim 2. Establish which HPV16E7 specific induced immune response(s) are most effective in controlling the development of HPV associated tumors in partially CD4 depleted line 19 mice.
Aim 2. 1 Examine the effect of different immunosuppression regimens on the development of HPV16E7 associated skin disease and tumors in line 19 mice.
Aim 2. 2 Examine the effect of partial CD4 depletion on the ability of different immunogens to induce E7 specific immune responses in vivo.
Aim 2. 3 Determine whether E7 primed CD8+ve Tc cells require CD4+ve T cells, either naive or primed, to effect epithelial tumor lysis in vivo Aim 2.4 Determine the effect of the expression of nef as a transgene in line 19 mice.
Aim 3. Establish whether premalignant HPV associated epithelial lesions are more susceptible to E7 specific immune surveillance than malignant HPV associated lesions Aim 3.1 Establish whether skin tumors expressing HPV16E7 differ in susceptibility to immune destruction according to whether they have developed in animals with normal or impaired immunity.
Aim 3. 2 Determine whether induction of HPV16E7 specific immunity favors survival of tumor clones with mutations in components of the antigen processing system.
|Frazer, I H; Thomas, R; Zhou, J et al. (1999) Potential strategies utilised by papillomavirus to evade host immunity. Immunol Rev 168:131-42|
|Hilditch-Maguire, P A; Lieppe, D M; West, D et al. (1999) T cell-mediated and non-specific inflammatory mechanisms contribute to the skin pathology of HPV 16 E6E7 transgenic mice. Intervirology 42:43-50|
|Frazer, I H; Fernando, G J; Fowler, N et al. (1998) Split tolerance to a viral antigen expressed in thymic epithelium and keratinocytes. Eur J Immunol 28:2791-800|
|Fernando, G J; Stewart, T J; Tindle, R W et al. (1998) Vaccine-induced Th1-type responses are dominant over Th2-type responses in the short term whereas pre-existing Th2 responses are dominant in the longer term. Scand J Immunol 47:459-65|
|Fernando, G J; Stewart, T J; Tindle, R W et al. (1998) Th2-type CD4+ cells neither enhance nor suppress antitumor CTL activity in a mouse tumor model. J Immunol 161:2421-7|