ASSOCIATION OF NKT- AND ACTIVATED CD25⁺ PERIPHERAL BLOOD LYMPHOCYTES WITH DISEASE FREE AND OVERALL SURVIVAL OF TRIPLE NEGATIVE BREAST CANCER PATIENTS

Background. We previously found that a decrease in the number of NKT cells and activated CD 25+ peripheral blood lymphocytes (PBLs) before neoadjuvant chemotherapy was associated with an increased likelihood of disease progression in patients with locally advanced triple-negative breast cancer (TN BC).

The purpose of this study was to determine the relationship between the initial number of NKT-and CD 25+ PBLs and relapsefree survival (RFS)/overall survival (OS ) in patients with TN BC who received neoadjuvant chemotherapy with cisplatin and paclitaxel followed by surgery.

Material and Methods. The study included patients with stage II and III TN BC. The follow-up time was 36 and 66.9 months. Immediately before chemotherapy, the percentage of CD 3+CD 16+CD 56+ (NKT) -, CD 25+- and CD 8+ PBLs was determined by flow cytometry. Statistical analysis of the data was carried out using the Statistics 7 software package. The Kaplan-Meier method was used to determine the relationship between immunological parameters and RFS/ OS .

Results. The decreased level of NKT cells before treatment was associated with a decrease in the 3-year RFS [Me: 20.1 (0.533 and 39.7) months] compared to that observed in patients with higher percentage of these cells than in the control (Me was not achieved). There were no statistically significant differences in the 3-year OS between the groups. The initially reduced number of CD 25+ lymphocytes in comparison with the control was associated with decreased rates of both RFS and OS . The difference in DFS and OS was more significant between the groups of patients who simultaneously had an increased initial number of both NKT and CD 25+ cells and patients in whom both cell populations were below normal levels.

Conclusion. The initial (prior to chemotherapy) number of NKT and activated CD 25+ PBLs can apparently be a predictive factor in TN BC patients, who received neoadjuvant chemotherapy with cisplatin and paclitaxel. 

1. Rivenbark A.G., O'Connor S.M., Coleman W.B. Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol. 2013 Oct; 183(4): 1113–1124. doi: 10.1016/j.ajpath.2013.08.002.

2. Teng M.W., Galon J., Fridman W.H., Smyth M.J. From mice to humans: developments in cancer immunoediting. J Clin Invest. 2015; 125(9): 3338–46. doi: 10.1172/JCI80004.

3. Finn O.J. A Believer’s Overview of Cancer Immunosurveillance and Immunotherapy. J Immunol. 2018 Jan 15; 200(2): 385–91. doi: 10.4049/jimmunol.1701302.

4. Huang Y., Ma C., Zhang Q., Ye J., Wang F., Zhang Y., Hunborg P., Varvares M.A., Hoft D.F., Hsueh E.C., Peng G. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget. 2015 Jul 10; 6(19): 17462–78. doi: 10.18632/oncotarget.3958.

5. Standish L.J., Sweet E.S., Novack J., Wenner C.A., Bridge C., Nelson A., Martzen M., Torkelson C. Breast cancer and the immune system. J Soc Integr Oncol. 2008 Fall; 6(4): 158–68.

6. Péguillet I., Milder M., Louis D., Vincent-Salomon A., Dorval T., Piperno-Neumann S., Scholl S.M., Lantz O. High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer. Cancer Res. 2014 Apr 15; 74(8): 2204–16. doi: 10.1158/0008-5472.CAN-13-2269.

7. Rühle P.F., Fietkau R., Gaipl U.S., Frey B. Development of a Modular Assay for Detailed Immunophenotyping of Peripheral Human Whole Blood Samples by Multicolor Flow Cytometry. Int J Mol Sci. 2016 Aug 11; 17(8): 1316. doi: 10.3390/ijms17081316.

8. Wu J., Waxman D.J. Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy. Cancer Lett. 2018 Apr 10; 419: 210–221. doi: 10.1016/j.canlet.2018.01.050.

9. Haikerwal S.J., Hagekyriakou J., MacManus M., Martin O.A., Haynes N.M. Building immunity to cancer with radiation therapy. Cancer Lett. 2015 Nov 28; 368(2): 198–208. doi: 10.1016/j.canlet.2015.01.009.

10. Burugu S., Asleh-Aburaya K., Nielsen T.O. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer. 2017 Jan; 24(1): 3–15. doi: 10.1007/s12282-016-0698-z.

11. Chertkova A.I., Slavina E.G., Shoua E.K., Zhukova L.G., Okruzhnova M.A., Nurtdinova V.A., Borunova A.A., Dzhgamadze N.T., Kadagidze Z.G. The main parameters of cellular immunity in patients with triple-negative breast cancer: relationship with efficiency of chemotherapy. Medical Immunology. 2018; 20(5): 667–680. (in Russian).

12. Bae E.A., Seo H., Kim I.K., Jeon I., Kang C.Y. Roles of NKT cells in cancer immunotherapy. Arch Pharm Res. 2019 Jul; 42(7): 543–548. doi: 10.1007/s12272-019-01139-8.

13. Giaccone G., Punt C.J., Ando Y., Ruijter R., Nishi N., Peters M., von Blomberg B.M., Scheper R.J., van der Vliet H.J., van den Eertwegh A.J., Roelvink M., Beijnen J., Zwierzina H., Pinedo H.M. A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res. 2002 Dec; 8(12): 3702–9.

14. Molling J.W., Langius J.A., Langendijk J.A., Leemans C.R., Bontkes H.J., van der Vliet H.J., von Blomberg B.M., Scheper R.J., van den Eertwegh A.J. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol. 2007 Mar 1; 25(7): 862–8. doi: 10.1200/JCO.2006.08.5787.

15. Casorati G., de Lalla C., Dellabona P. Invariant natural killer T cells reconstitution and the control of leukemia relapse in pediatric haploidentical hematopoietic stem cell transplantation. Oncoimmunology. 2012 May 1; 1(3): 355–357. doi: 10.4161/onci.18399.

16. Benczik M., Gaffen S.L. The interleukin (IL)-2 family cytokines: survival and proliferation signaling pathways in T lymphocytes. Immunol Invest. 2004 May; 33(2): 109–42. doi: 10.1081/imm-120030732.

17. Ellery J.M., Nicholls P.J. Possible mechanism for the alpha subunit of the interleukin-2 receptor (CD25) to influence interleukin-2 receptor signal transduction. Immunol Cell Biol. 2002 Aug; 80(4): 351–7. doi: 10.1046/j.1440-1711.2002.01097.x.