Immune activation in cervical neoplasia

Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease

Allan Hildesheim, Mark H. Schiffman, Taku Tsukui, Christine A. Swanson, Joseph Lucci, David R. Scott, Andrew G. Glass, Brenda B. Rush, Attila T. Lorincz, Alice Corrigan, Robert D. Burk, Kay Helgesen, Richard A. Houghten, Mark E. Sherman, Robert J. Kurman, Jay A. Berzofsky, Tim R. Kramer

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Abstract

In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL- 2R levels were found to increase with increasing disease severity (P(trend) = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among HSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as ≤450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (P(trend) = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (P(trend) = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2- mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

Original languageEnglish (US)
Pages (from-to)807-813
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume6
Issue number10
StatePublished - 1997

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Interleukin-2 Receptors
Neoplasms
Interleukin-2
Human papillomavirus 16
Peptides
Papillomavirus Infections
Disease Progression
Virus Diseases

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Hildesheim, A., Schiffman, M. H., Tsukui, T., Swanson, C. A., Lucci, J., Scott, D. R., ... Kramer, T. R. (1997). Immune activation in cervical neoplasia: Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease. Cancer Epidemiology Biomarkers and Prevention, 6(10), 807-813.

Immune activation in cervical neoplasia : Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease. / Hildesheim, Allan; Schiffman, Mark H.; Tsukui, Taku; Swanson, Christine A.; Lucci, Joseph; Scott, David R.; Glass, Andrew G.; Rush, Brenda B.; Lorincz, Attila T.; Corrigan, Alice; Burk, Robert D.; Helgesen, Kay; Houghten, Richard A.; Sherman, Mark E.; Kurman, Robert J.; Berzofsky, Jay A.; Kramer, Tim R.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 6, No. 10, 1997, p. 807-813.

Research output: Contribution to journalArticle

Hildesheim, A, Schiffman, MH, Tsukui, T, Swanson, CA, Lucci, J, Scott, DR, Glass, AG, Rush, BB, Lorincz, AT, Corrigan, A, Burk, RD, Helgesen, K, Houghten, RA, Sherman, ME, Kurman, RJ, Berzofsky, JA & Kramer, TR 1997, 'Immune activation in cervical neoplasia: Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease', Cancer Epidemiology Biomarkers and Prevention, vol. 6, no. 10, pp. 807-813.
Hildesheim, Allan ; Schiffman, Mark H. ; Tsukui, Taku ; Swanson, Christine A. ; Lucci, Joseph ; Scott, David R. ; Glass, Andrew G. ; Rush, Brenda B. ; Lorincz, Attila T. ; Corrigan, Alice ; Burk, Robert D. ; Helgesen, Kay ; Houghten, Richard A. ; Sherman, Mark E. ; Kurman, Robert J. ; Berzofsky, Jay A. ; Kramer, Tim R. / Immune activation in cervical neoplasia : Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease. In: Cancer Epidemiology Biomarkers and Prevention. 1997 ; Vol. 6, No. 10. pp. 807-813.
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author = "Allan Hildesheim and Schiffman, {Mark H.} and Taku Tsukui and Swanson, {Christine A.} and Joseph Lucci and Scott, {David R.} and Glass, {Andrew G.} and Rush, {Brenda B.} and Lorincz, {Attila T.} and Alice Corrigan and Burk, {Robert D.} and Kay Helgesen and Houghten, {Richard A.} and Sherman, {Mark E.} and Kurman, {Robert J.} and Berzofsky, {Jay A.} and Kramer, {Tim R.}",
year = "1997",
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TY - JOUR

T1 - Immune activation in cervical neoplasia

T2 - Cross-sectional association between plasma soluble interleukin 2 receptor levels and disease

AU - Hildesheim, Allan

AU - Schiffman, Mark H.

AU - Tsukui, Taku

AU - Swanson, Christine A.

AU - Lucci, Joseph

AU - Scott, David R.

AU - Glass, Andrew G.

AU - Rush, Brenda B.

AU - Lorincz, Attila T.

AU - Corrigan, Alice

AU - Burk, Robert D.

AU - Helgesen, Kay

AU - Houghten, Richard A.

AU - Sherman, Mark E.

AU - Kurman, Robert J.

AU - Berzofsky, Jay A.

AU - Kramer, Tim R.

PY - 1997

Y1 - 1997

N2 - In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL- 2R levels were found to increase with increasing disease severity (P(trend) = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among HSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as ≤450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (P(trend) = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (P(trend) = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2- mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

AB - In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL- 2R levels were found to increase with increasing disease severity (P(trend) = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among HSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as ≤450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (P(trend) = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (P(trend) = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2- mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

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