A study of women with cervical intraepithelial neoplasia (CIN), a condition that often precedes invasive cervical cancer and is linked to infection with certain strains of human papillomavirus (HPV), found that those with the most extensive infections also had altered production of cytokines. The study is reported in the February 5th issue of the Journal of the National Cancer Institute.
As Mario Clerici, md, Università degli Studi di Milano, Italy, and colleagues explain, several of the more than 23 strains of HPV are known to be associated with the development of human cancers. Cervical cancer, of which there are some 15,000 new cases in the United States each year, is one such malignancy.
Human papillomavirus-associated CIN is a frequent precursor of invasive cancer, say the authors, but it is also believed that host factors are critical in regulating the growth of HPV-linked tumors. Certain cytokines that modulate immune function may be of particular importance, they add. According to the authors, the so-called type 1 cytokines interleukin-2 (IL-2) and inter- feron-gamma (IFN-gamma) stimulate immune response and can limit tumor growth; conversely, the type 2 cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) inhibit immune response and can stimulate tumor growth.
Different Immunologic Profiles Correspond to Extent of Infection
In this study, Clerici and coworkers assessed the extent and type of HPV infection in 30 women (median age, 34.5 years) diagnosed with CIN and in 10 healthy age-matched control subjects. In addition, they analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) extracted from blood samples provided by each woman.
Specifically, IL-2 production was measured in PBMCs exposed to soluble influenza antigen (to assess blood system-mediated immune response) or to a known stimulus of cell-mediated immune response, human leukocyte antigen (HLA) alloantigen. In addition, the researchers measured PBMC production of IL-2, IFN-gamma, IL-4, and IL-10 following stimulation with the mitogen phytohemagglutinin, a substance known to induce the release of immune response mediators by lymphocytes.
High-grade CIN associated with HPV infection was detected in all 30 case patients, and cancer-associated HPV types 16 or 18 were detected in the cervical tissue of 21 (70%) of the 30 women with CIN. Human papillomavirus infection that had spread to other sites in the lower genital tract, resulting in more extensive disease, was detected in 16 (53%) of the 30 women with CIN; the remainder had HPV infection limited to the cervix.
Interleukin-2 production by PBMCs following stimulation with either influenza or HLA alloantigen was reduced in the group with extensive disease, as compared with those with local disease or the healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was higher in the women with extensive disease than in the other two groups. The highest production of IL-4 and IL-10 was detected in patients with HPV infection extending beyond the genital tract.
Clerici and coworkers conclude that CIN is characterized by different immunologic profiles, corresponding to the extent of infection of the lower genital tract. The study results suggest a pronounced shift from type 1 to type 2 cytokine production, such that the production of type 1 cytokines that mainly enhance potentially protective cell-mediated immunity appears to be defective in women with extensive HPV infection. These data reinforce the need to analyze immune dysregulation in CIN patients and suggest the possible usefulness of cytokine testing for assessing prognosis and deciding whether cytokine-based therapy is indicated.
Role of Cytokines Merits Further Study
In an editorial accompanying this report, T.C. Wu, md, phd, and Robert J. Kurman, md, The Johns Hopkins University, Baltimore, say that the study by Clerici and colleagues adds to our growing understanding of the mechanisms by which the immune system mediates the behavior of HPV-associated cancers. Cytokine therapy, they believe, may have the potential to bolster diminished immune function associated with the progression of diseases influenced by inappropriate cytokine production. Wu and Kurman recommend further studies to elucidate precisely how cytokine production is regulated in response to HPV infection, as well as the role of cytokines in the critical step between infection and tumor development.