BioWorld International Correspondent

LONDON - New insights into immune system response to human papillomavirus (HPV) will help direct work aimed at making a therapeutic vaccine for cervical cancer.

Researchers studying how the immune response differs between women infected with HPV who have cancer and those who have not developed disease said the findings will provide vital clues about which viral proteins to include in a potential vaccine.

Jane Steele, research fellow at the Cancer Research UK Institute for Cancer Studies at the University of Birmingham, told BioWorld International: "In those women where the immune system seems to be keeping the infection at bay, and who do not progress to develop cancer, it is going to be important to know how that is happening. We have now identified which components of the immune system are important in fighting the virus, and we can use that knowledge to design a therapeutic vaccine."

Cervical cancer is the 11th most common cancer in the UK - in 2002, it caused 1,120 deaths. Each year, 274,000 women die from it worldwide.

About 99 percent of all cervical cancers are linked to infection with HPV. Some types of HPV cause only genital warts, but HPV 16, 18, 30 and 33 commonly are found in cervical cancers. The study by Steele and her colleagues looked specifically at HPV 16 because it is present in up to 70 percent of cervical cancers.

Vaccines to prevent HPV infection, and thus prevent cervical cancer, are being developed and might be licensed soon. However, those vaccines will not help women who already are infected with HPV, or those who do not receive a vaccine once it becomes available. For those groups, researchers have been trying to develop a vaccine that can be given after cervical disease has started to develop, that will trigger a strong immune response to the virus-infected cells and that will help the body eliminate or control the abnormal cells.

Steele said, "A vaccine is an ideal way to tackle this problem because the virus in the cancer cells provides the perfect target - one that is not present in normal cells."

She and her colleagues took blood samples from healthy women, from those with low-grade cervical abnormalities, from those with high-grade cervical abnormalities and from those with cervical cancer. They then presented the women's peripheral blood lymphocytes with different antigens from HPV 16 and evaluated how the cells of the immune system responded.

The results appeared in the July 19, 2005, issue of British Journal of Cancer in a paper titled "T-Cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia."

Steele said: "We saw differences in the immune responses of these groups. The cells from women who progressed to high-grade disease or who had cancer responded differently to those who had low-grade disease. T-helper cells from women with high-grade disease responded less well to the viral peptides."

The study also found that there was a strong immune response to the viral protein E6, but not to some of the other proteins and peptides.

"This response was strong in all groups, so it may not dictate how successfully women deal with HPV infection," Steele said. Although many projects aiming to develop a therapeutic vaccine for cervical cancer have concentrated on E6, she added, the finding might suggest that it is not the best HPV component to include.

Why women who become infected with HPV 16 still develop cervical cancer despite a strong immune response to the virus remains a mystery. The study does, however, provide some pointers to what is happening.

"We believe that the HPV-infected tumor cells become resistant to attack by the immune system," Steele said. "We think the virus manipulates the cells, down-regulating the machinery that normally allows them to process antigens and present antigens on their surfaces. These cells do not express all the molecules of the major histocompatibility complex, which are involved in these processes, that you would normally expect."

The team wants to pursue that line of inquiry. "If you are trying to vaccinate people to stimulate the immune response, there is no point in doing this if the cells can hide from the attack," Steele concluded.

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