Study of signaling pathways triggered by and biological effects of CD40 in cervical tumors.

Abstract

Cervical cancer is the second cause for women's death by cancer among Brazilian women. Human Papillomavirus, HPV, is the main etiologic factor for the development of these tumors. HPV are small DNA tumor virus, non-enveloped and epitheliotropic. They infect skin and mucosa causing, depending on the virus type warts and papillomas or malignant tumors.Upon infection, early viral proteins are expressed. E6 and E7 are bona fide oncoproteins responsible for several mechanisms of viral immune evasion. The immune system has a fundamental role in controlling HPV associated lesions and infection. This was exposed by several studies demonstrating correlation between risk of disease progression and infection and immune deficiencies, such as HIV infection. Adaptative anti-viral responses are CD4 Th1, observed in asymptomatic women. However, in women with cervical cancer, specific regulatory T cells inhibit anti-tumor effector T cells. Our laboratory and others have demonstrated that HPV associated tumors recruit and determine the phenotype of antigen presenting cells, which by its turn, induce T cell regulatory responses, inhibiting anti-tumor activity. However, we do not understand the complete mechanisms by which these steps take place, and we believe that understanding these mechanisms, will help us to design tools for immune therapy.CD40/CD40L pathways are important for antigen presenting cells/T cells activation, respectively. Although data from the literature show expression of CD40 in keratinocytes and dendritic cells in HPV associated tumors, the role of these molecules is far from elucidated. Some authors see the expression of these molecules as a potential target for therapy, while others have associated CD40 expression with chemotherapy resistance. In our experimental model, we have observed a therapeutic action of activation of CD40 in the presence of previously activated lymphocytes.The objective of this project is to study the state of activation of the CD40 pathway in the absence or presence of specific agonists, in both keratinocytes and inflammatory infiltrate tumor populations. Moreover, we will verify if upon activation of CD40 pathway, antigen presenting cells will be able to activate Th1 and cytotoxic responses in T cells. Our project not only will help to elucidate the role of CD40 in the biology of cervical tumors, but also create opportunities for anti-tumor therapy.