Immunohistochemical Expression of B7-H4 in Ovarian Tumors

Marvi Raza, Fouzia Shaikh, Santosh Kumar Sidhwani, Faraz Ahmed Baig, Rehan Ahmed Siddiqui


In cancers, inflammation, and autoimmune illnesses, the coinhibitory molecule B7-H4, an important member of the B7 family, is inappropriately produced. By reducing T cell proliferation, cytokine release, and cell cycle, B7-H4 negatively controls T cell immune response and promotes immunological escape. Furthermore, B7-H4 plays a critical function in carcinogenesis and tumor growth, including cell proliferation, anti-apoptosis, tumor, invasion and metastasis development. As a result, B7-H4 has been identified as a potential therapeutic target for malignancies, inflammation, autoimmune disorders, and organ transplantation. So, the objective of the current study was to evaluate the immunohistochemical expression of B7-H4 in different ovarian tumor histological variants that would be used for target therapy in the future.  This cross-sectional study was conducted at Ziauddin University and Hospital North campus, comprised of 71 cases. Consent and demographic details were obtained before the selection of cases. The obtained data were analyzed statistically via SPSS version 21.  Positive IHC expression was seen in 48 of 71 ovarian cancers (67.6%). The majority of B7-H4 IHC positive patients (22/48; 45.8%) were malignant, with benign (20/48; 41.7%) and borderline (6/48; 12.5%) tumors following closely behind, indicating a statistically significant link between B7-H4 and ovarian cancers (p=0.004). B7-H4 protein expression was also found in some unusual ovarian tumor morphological forms, such as 5/5 dysgerminoma and 2/2 Brenner tumor of the ovaries. These uncommon variations are also statistically linked to B7-H4 protein expression (p-value: 0.011). Most positive samples had protein expression strength of 1 on a scale of 4 with a significant statistical estimate of p-value 0.015.


Keywords: B7-H4, ovarian tumors, serous tumor, mucinous tumor, Brenner tumor.

Full Text:



RASMUSSEN C.B., KJAER S.K., ALBIERI V., BANDERA E.V., DOHERTY J.A., HØGDALL E., PENELOPE WEBB M., JORDAN S.J., ROSSING M.A. WICKLUND K.G., GOODMAN M.T., MODUGNO F., MOYSICH K.B., NESS R.B., EDWARDS R.P., SCHILDKRAUT J.M., BERCHUCK A., OLSON S.H., KIEMENEY LAMBERTUS A., LEON F.A.G. MASSUGER, NAROD S.A., PHELAN C.M., ANTON-CULVER H., ZIOGAS A., WU A.H., PEARCE C.L., RISCH H.A., and JENSEN A. Pelvic inflammatory disease and the risk of ovarian cancer and borderline ovarian tumors: a pooled analysis of 13 case-control studies. American Journal of Epidemiology, 2017, 185(1): 8-20.

FLICEK K., VANBUREN W., DUDIAK K., and LAHKMAN Y. Borderline epithelial ovarian tumors: what the radiologist should know. Abdominal Radiology, 2021, 46(6): 2350-2366.

TORRE L.A., TRABERT B., DESANTIS C.E., MILLER K.D., SAMIMI G., RUNOWICZ C.D., GAUDET M.M., JEMAL A., and SIEGEL R.L. Ovarian cancer statistics, 2018. Cancer Journal for Clinicians, 2018, 68(4): 284-296.

ALVI Q., BALOCH G.M., CHINNA K., and DABBAGH A. Lifestyle and reproductive health: the aetiology of ovarian cancer in Pakistan. F1000Research, 2020, 9.

PERVEZ S., JABBAR A.A., HAIDER G., ASHRAF S., QURESHI M.A., LATEEF F., BASHIR I., ZAIDI M., KHURSHID M., QURAISHY M.S., SIDDIQI T., RIZWAN U., SAQIB M.A.N., MEMON M.A., ALAM E., and QURESHI H. Karachi Cancer Registry: Age-standardized incidence rate by age-group and gender in a Megacity of Pakistan. Asian Pacific Journal of Cancer Prevention, 2020, 21(11): 32-51.

LA VECCHIA C. Ovarian cancer: epidemiology and risk factors. European Journal of Cancer Prevention, 2017, 26(1): 55-62.

MOMENIMOVAHED Z., TIZNOBAIK A., TAHERI S., and SALEHINIYA H. Ovarian cancer in the world: epidemiology and risk factors. International Journal of Women's Health, 2019, 11: 287.

LU H-M., LI S., BLACK M.H., LEE S., HOINESS R., WU S., WENBO M.U., HUETHER R., CHEN J., SRIDHAR S., TIAN Y., MCFARLAND R.L, DOLINSKY J., DAVIS B.T., MEXAL S., DUNLOP C.S., and ELLIOTT A. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. Oncology Journal of American Medical Association, 2019, 5(1): 51-57.

DE ALMEIDA CHUFFA L.G., LUPI-JÚNIOR L.A., COSTA A.B., DE ARRUDA AMORIM J.P., and SEIVA F.R.F. The role of sex hormones and steroid receptors on female reproductive cancers. Steroids, 2017, 118: 93-108.

DOCHEZ V., CAILLON H., VAUCEL E., DIMET J., WINER N., and DUCARME G. Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review. Journal of Ovarian Research, 2019, 12(1): 1-9.

BASAK B., MONDAL S.K., and DEBNATH S. WT1, Bcl-2, Ki-67 and Her2/Neu as diagnostic and prognostic immuno markers in ovarian serous and endometrioid carcinoma. Frontiers in Bioengineering and Biotechnology, 2021. [Online]. Available from: |

PĂVĂLEANU I., LOZNEANU L., BALAN R.A., GIUŞCĂ S.E., AVĂDĂNEI E-R., CĂRUNTU I-D., and AMALINEI C. Insights into molecular pathways of endometriosis and endometriosis-related ovarian carcinoma. Romanian Journal of Morphology and Embryology, 2020, 61(3): 739.

WANG J-Y. & WANG W-P. B7-H4, a promising target for immunotherapy. Cellular Immunology, 2020, 347: 104008.

WU L., DENG W-W., YU G-T., MAO L., BU L-L., MA S-R., LIU B., ZHANG W.F., and SUN Z.J. B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma. Cancer Immunology, Immunotherapy, 2016, 65(9): 1035-1045.

SONG X., ZHOU Z., LI H., XUE Y., LU X., BAHAR I., and WAN Y. Pharmacologic suppression of B7-H4 glycosylation restores antitumor immunity in immune-cold breast cancers. Cancer Discovery, 2020, 10(12): 1872-1893.

DING S., LV X., LIU Z., ZHAN S., XU Y., ZHANG X., LIU C., and CAO L. Overexpression of B7-H4 is associated with infiltrating immune cells and poor prognosis in metastatic colorectal cancer. International Immunopharmacology, 2021, 90: 107144.

DAVIDSON W., MADAN R., O'NEIL M., TAWFIK O.W., and FAN F. Utility of peritoneal washing cytology in staging and prognosis of ovarian and fallopian tube neoplasms: a 10-year retrospective analysis. Annals of Diagnostic Pathology, 2016, 22: 54-57.

OUZAID I. Exploration biologique de la progression du cancer du rein à haut risque: analyse ancillaire de la cohorte française de l’essai S-TRAC. Université Rennes 1, 2021.

HUANG H., LI C., and REN G. Clinical significance of the B7-H4 as a novel prognostic marker in breast cancer. Gene, 2017, 623:24-28.

LUBORSKY J., BARUA A., EDASSERY S., BAHR J.M., and EDASSERY S.L. Inflammasome expression is higher in ovarian tumors than in normal ovary. Public Library of Science One, 2020, 15(1): e0227081.

PODOJIL J.R., GLASER A.P., BAKER D., COURTOIS E.T., FANTINI D., YU Y., EATON V., SIVAJOTHI S., CHIANG M., DAS A., MCLAUGHLIN K.A., ROBSON P., MILLER S.D., and MEEKS J.J. Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma. Oncoimmunology, 2020, 9(1): 1744897.

PODOJIL J.R. & MILLER S.D. Potential targeting of B7‐H4 for the treatment of cancer. Immunological Reviews, 2017, 276(1): 40-51.

CHOI I-H., ZHU G., SICA G.L., STROME S.E., CHEVILLE J.C., LAU J.S., ZHU Y., FLIES D.B., TAMADA K., and CHEN L. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. Journal of Immunology, 2003, 171(9): 4650-4654.

TRINGLER B., LIU W., CORRAL L., TORKKO K.C., ENOMOTO T., DAVIDSON S., LUCIA M.S., HEINZ D.E., PAPKOFF J., and SHROYER K.R. B7-H4 overexpression in ovarian tumors. Gynecologic Oncology, 2006, 100(1): 44-52.

SIMON I., ZHUO S., CORRAL L., DIAMANDIS E.P., SARNO M.J., WOLFERT R.L., and KIM N.W. B7-H4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Research, 2006, 66(3): 1570-1575.

PEARCE O.M. & LÄUBLI H. A sweet approach to heat up cancer response to immunotherapy. Cancer Discovery, 2020, 10(12): 1789-1790.


  • There are currently no refbacks.