Expression of Programmed Death Ligand-1 and Correlation with Clinicopathological Features and CD8 Infiltration in Breast Cancer
Background: Breast cancer (BC) is considered one of the most diversified types of tumors, characterized by a high mutational burden in the tumor milieu and a lack of immune cell makeup. The programmed death receptor-1 (PD -1)/programmed death ligand-1 (PD -L1) axis has been identified as a new target in the field of immunotherapy because, when activated, they worsen the future scenarios of the disease by helping tumor cells (TC) to escape immune surveillance. This study aims to investigate the expression of PD-L1 in BC tissues from Sudanese women and correlate the expression with clinicopathological features and the infiltration of CD8+T lymphocytes by immunohistochemistry (IHC).
Methods: One hundred and fifty archived BC blocks were collected from the National Public Health Laboratory from January 2019 to August 2020. Data regarding age, TNM staging, grade, and hormonal status were considered. Tissue sections were examined using IHC to determine the expression of PD-L1 and CD8.
Results: Among one hundred and fifty BC samples, 73 (48.7%) were TNBCs, and 77 (51.3%) were hormone-positive BCs. PDL-1 was significantly associated with BC subtypes, especially TNBCs (P = 0.001), a similar significant association was shown with CD8 infiltration (P = 0.006). None of the clinicopathological features was associated with PD-L1 expression.
Conclusion: PD-L1 expression is strongly associated with TNBC’s and linked to CD8+ cells infiltration to the tumor milieu. Moreover, no correlation has been observed between the expression of PD-L1 and clinicopathological features in this study.
immune therapy, PD-1, PD-L1, TILs infiltration, TNBCs, immune-check points blockers
 Stovgaard, E. S., Dyhl-Polk, A., Roslind, A., Balslev, E., & Nielsen, D. (2019). PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: A systematic review. Breast Cancer Research and Treatment, 174(3), 571–584.
 Huang, X., Wang, X., Qian, H., Jin, X., Jiang, G. (2021). Expression of PD-L1 and BRCA1 in triple-negative breast cancer patients and relationship with clinicopathological characteristics. Evid Based Complement Alternat Med, 2021; 5314016.
 Perou, C. M., Sørlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., Rees, C. A., Pollack, J. R., Ross, D. T., Johnsen, H., Akslen, L. A., Fluge, O., Pergamenschikov, A., Williams, C., Zhu, S. X., Lønning, P. E., Børresen-Dale, A. L., Brown, P. O., & Botstein, D. (2000). Molecular portraits of human breast tumours. Nature, 406(6797), 747–752.
 Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 12(4), 252–264.
 Taube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., Chen, S., Klein, A. P., Pardoll, D. M., Topalian, S. L., Chen, L. (2012). Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Translational Med, 4(127), 127ra37-ra37.
 Bedognetti, D., Hendrickx, W., Marincola, F. M., & Miller, L. D. (2015). Prognostic and predictive immune gene signatures in breast cancer. Current Opinion in Oncology, 27(6), 433–444.
 Buisseret, L., Garaud, S., de Wind, A., Van den Eynden, G., Boisson, A., Solinas, C., Gu-Trantien, C., Naveaux, C., Lodewyckx, J. N., Duvillier, H., Craciun, L., Veys, I., Larsimont, D., Piccart-Gebhart, M., Stagg, J., Sotiriou, C., & Willard-Gallo, K. (2016). Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer. OncoImmunology, 6(1), e1257452.
 Schalper, K. A. (2014). PD-L1 expression and tumor-infiltrating lymphocytes: Revisiting the antitumor immune response potential in breast cancer. OncoImmunology, 3, e29288.
 Wimberly, H., Brown, J. R., Schalper, K., Haack, H., Silver, M. R., Nixon, C., Bossuyt, V., Pusztai, L., Lannin, D. R., & Rimm, D. L. (2015). PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunology Research, 3(4), 326–332.
 Schalper, K. A., Velcheti, V., Carvajal, D., Wimberly, H., Brown, J., Pusztai, L., & Rimm, D. L. (2014). In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clinical Cancer Research, 20(10), 2773– 2782.
 Ayoub, N. M., Fares, M., Marji, R., Al Bashir, S. M., & Yaghan, R. J. (2021). Programmed Death-Ligand 1 Expression in Breast Cancer Patients: Clinicopathological Associations from a Single-Institution Study. Breast Cancer (Dove Medical Press), 13, 603– 615.
 Huang, W., Ran, R., Shao, B., & Li, H. (2019). Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: A meta-analysis. Breast Cancer Research and Treatment, 178(1), 17–33.
 Matikas, A., Zerdes, I., Lövrot, J., Richard, F., Sotiriou, C., Bergh, J., Valachis, A., & Foukakis, T. (2019). Prognostic implications of PD-L1 expression in breast cancer: Systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data. Clinical Cancer Research, 25(18), 5717–5726.
 Li, Z., Dong, P., Ren, M., Song, Y., Qian, X., Yang, Y., Li, S., Zhang, X., & Liu, F. (2016). PD-L1 expression is associated with tumor FOXP3(+) regulatory T-Cell infiltration of breast cancer and poor prognosis of patient. Journal of Cancer, 7(7), 784–793.
 Ferlay, J., Ervik, M., Lam, F., Colombet, M., Mery, L., Piñeros, M., . . .. (2019). Global cancer observatory: Cancer tomorrow. International Agency for Research on Cancer.
 Saeed, I. E., Weng, H. Y., Mohamed, K. H., & Mohammed, S. I. (2014). Cancer incidence in Khartoum, Sudan: First results from the Cancer Registry, 2009-2010. Cancer Medicine, 3(4), 1075–1084.
 Zhou, T., Xu, D., Tang, B., Ren, Y., Han, Y., Liang, G., Wang, J., & Wang, L. (2018). Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis. Anti- Cancer Drugs, 29(9), 904–910.
 Evangelou, Z., Papoudou-Bai, A., Karpathiou, G., Kourea, H., Kamina, S., Goussia A, Harissis H, Peschos D, Batistatou A. PD-L1 expression and tumor-infiltrating lymphocytes in breast cancer: Clinicopathological analysis in women younger than 40 years old. In vivo 2020, 34(2), 639–647.
 Lou, J., Zhou, Y., Huang, J., & Qian, X. (2017). Relationship between PD-L1 expression and clinical characteristics in patients with breast invasive ductal carcinoma. Open Medicine (Warsaw), 12(1), 288–292.
 Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., Antipin, Y., Reva, B., Goldberg, A. P., Sander, C., & Schultz, N. (2012). The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discovery, 2(5), 401–404.
 Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., Cerami, E., Sander, C., & Schultz, N. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling, 6(269), pl1.
 Tang, G., Cho, M., & Wang, X. (2022). OncoDB: An interactive online database for analysis of gene expression and viral infection in cancer. Nucleic Acids Research, 50(D1), D1334–D1339.
 Kassardjian, A., Shintaku, P. I., & Moatamed, N. A. (2018). Expression of immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), in female breast carcinomas. PLoS One, 13(4), e0195958.
 Qin, T., Zeng, Y. D., Qin, G., Xu, F., Lu, J. B., Fang, W. F., Xue, C., Zhan, J. H., Zhang, X. K., Zheng, Q. F., Peng, R. J., Yuan, Z. Y., Zhang, L., & Wang, S. S. (2015). High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget, 6(32), 33972–33981.
 Carter, J. M., Polley, M. C., Leon-Ferre, R. A., Sinnwell, J., Thompson, K. J., Wang, X., Ma, Y., Zahrieh, D., Kachergus, J. M., Solanki, M., Boughey, J. C., Liu, M. C., Ingle, J. N., Kalari, K. R., Couch, F. J., Thompson, E. A., & Goetz, M. P. (2021). Characteristics and spatially defined immune (micro)landscapes of early-stage PD-L1-positive triplenegative breast cancer. Clinical Cancer Research, 27(20), 5628–5637.
 Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., Qiao, N., Wu, Y., Harrington, S., Su, X., Wang, Y., Gonzalez-Angulo, A. M., Akcakanat, A., Chawla, A., Curran, M., Hwu, P., Sharma, P., Litton, J. K., Molldrem, J. J., & Alatrash, G. (2014). PD-L1 expression in triple-negative breast cancer. Cancer Immunology Research, 2(4), 361–370.
 Kongtawelert, P., Wudtiwai, B., Shwe, T. H., Pothacharoen, P., & Phitak, T. (2020). Inhibition of programmed death ligand 1 (PD-L1) expression in breast cancer cells by sesamin. International Immunopharmacology, 86, 106759.
 Bharadwa, K. R., Dasgupta, K., Narayana, S. M., Ramachandra, C., Babu, S. M. C., Rangarajan, A., & Kumar, R. V. (2021). PD-1 and PD-L1 expression in Indian women with breast cancer. European Journal of Breast Health, 18(1), 21–29.
 Hou, Y., Nitta, H., Wei, L., Banks, P. M., Lustberg, M., Wesolowski, R., Ramaswamy, B., Parwani, A. V., & Li, Z. (2018). PD-L1 expression and CD8-positive T cells are associated with favorable survival in HER2-positive invasive breast cancer. The Breast Journal, 24(6), 911–919.
 Shenasa, E., Stovgaard, E. S., Jensen, M.-B., Asleh, K., Riaz, N., Gao, D., Leung, S., Ejlertsen, B., Laenkholm, A. V., & Nielsen, T. O. (2022). Neither tumor-infiltrating lymphocytes nor cytotoxic t cells predict enhanced benefit from chemotherapy in the DBCG77B Phase III clinical trial. Cancers (Basel), 14(15), 3808.