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
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.