Extent of Genital Infection With Cancer-Linked HPV May Relate to the Type of Immune Response

A study of women with cervical intraepithelial neoplasia (CIN), a conditionthat often precedes invasive cervical cancer and is linked to infectionwith certain strains of human papillomavirus (HPV), found that those withthe most extensive infections also had altered production of cytokines.The study is reported in the February 5th issue of the Journal of theNational Cancer Institute.

As Mario Clerici, md, Università degli Studi di Milano, Italy,and colleagues explain, several of the more than 23 strains of HPV areknown to be associated with the development of human cancers. Cervicalcancer, of which there are some 15,000 new cases in the United States eachyear, is one such malignancy.

Human papillomavirus-associated CIN is a frequent precursor of invasivecancer, say the authors, but it is also believed that host factors arecritical in regulating the growth of HPV-linked tumors. Certain cytokinesthat 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 andcan limit tumor growth; conversely, the type 2 cytokines interleukin-4(IL-4) and interleukin-10 (IL-10) inhibit immune response and can stimulatetumor growth.

Different Immunologic Profiles Correspond to Extent of Infection

In this study, Clerici and coworkers assessed the extent and type ofHPV infection in 30 women (median age, 34.5 years) diagnosed with CIN andin 10 healthy age-matched control subjects. In addition, they analyzedthe 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 solubleinfluenza antigen (to assess blood system-mediated immune response) orto a known stimulus of cell-mediated immune response, human leukocyte antigen(HLA) alloantigen. In addition, the researchers measured PBMC productionof IL-2, IFN-gamma, IL-4, and IL-10 following stimulation with the mitogenphytohemagglutinin, a substance known to induce the release of immune responsemediators by lymphocytes.

High-grade CIN associated with HPV infection was detected in all 30case patients, and cancer-associated HPV types 16 or 18 were detected inthe cervical tissue of 21 (70%) of the 30 women with CIN. Human papillomavirusinfection that had spread to other sites in the lower genital tract, resultingin more extensive disease, was detected in 16 (53%) of the 30 women withCIN; the remainder had HPV infection limited to the cervix.

Interleukin-2 production by PBMCs following stimulation with eitherinfluenza 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 stimulationwas 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 withHPV infection extending beyond the genital tract.

Clerici and coworkers conclude that CIN is characterized by differentimmunologic profiles, corresponding to the extent of infection of the lowergenital tract. The study results suggest a pronounced shift from type 1to type 2 cytokine production, such that the production of type 1 cytokinesthat mainly enhance potentially protective cell-mediated immunity appearsto be defective in women with extensive HPV infection. These data reinforcethe need to analyze immune dysregulation in CIN patients and suggest thepossible usefulness of cytokine testing for assessing prognosis and decidingwhether cytokine-based therapy is indicated.

Role of Cytokines Merits Further Study

In an editorial accompanying this report, T.C. Wu, md, phd, and RobertJ. Kurman, md, The Johns Hopkins University, Baltimore, say that the studyby Clerici and colleagues adds to our growing understanding of the mechanismsby which the immune system mediates the behavior of HPV-associated cancers.Cytokine therapy, they believe, may have the potential to bolster diminishedimmune function associated with the progression of diseases influencedby inappropriate cytokine production. Wu and Kurman recommend further studiesto elucidate precisely how cytokine production is regulated in responseto HPV infection, as well as the role of cytokines in the critical stepbetween infection and tumor development.