QUANTITATIVE EXPRESSION FEATURES OF PD-1 AND TIM-3 CHECKPOINT MOLECULE RECEPTORS ON CD4⁺ AND CD8⁺ T-CELLS IN BREAST CANCER OF VARYING PROGRESSION DEGREES

During the course of chronic viral infections or tumor growth, due to the constant presence of antigen and inflammation, a dysfunctional state of T-cells called exhaustion occurs. Factors associated with T-cell exhaustion include an increase in the expression of various inhibitory receptors, also known as checkpoint molecules, which leads to inhibition of the proliferation and production of mediators such as IL-2, IFNγ, and TNFα.

The TIM-3 molecule is expressed on a variety of immune cells, including dendritic cells, macrophages, and T-cells, and mediates suppressive activity on immune cells. Sustained expression of the PD-1 receptor on T-lymphocytes is also associated with the exhaustion phenotype, while it remains unclear how the expression of these inhibitory receptors normally differs from that in pathological conditions of the body, which are characterized by an increase in the number of exhausted T-cells.

The aim of the study was to determine the relative and absolute number of T-cells expressing PD-1 and TIM-3, as well as the number of PD-1 and TIM-3 molecules on the surface of CD4⁺ and CD8⁺T-cells in healthy donors and breast cancer (BC) patients. Group of BC patients were conditionally divided into two groups depending on the degree of disease progression into patients with primary (without metastases) and metastatic BC.

As a result of the study, it was shown that an increase in the absolute number of PD-1⁺CD4⁺T-cells is observed in breast cancer patients. The absolute number of molecules per cell is also higher in BC patients compared to healthy donors. For patients, a tendency towards an increase in the absolute number of TIM-3⁺CD4⁺T-cells was shown in comparison with healthy donors and in a row from primary disease to metastatic BC.

Thus, differences in the expression pattern of TIM-3 and PD-1 checkpoint molecules are observed when comparing the norm and malignant pathology of the breast, and can become an important marker of the functional state of T-lymphocytes in BC patients. 

1. Ager C.R., Obradovic A.Z., Arriaga J.M., Chaimowitz M.G., Califano A., Abate-Shen C., Drake C.G. Longitudinal immune profiling reveals unique myeloid and T-cell phenotypes associated with spontaneous immunoediting in a prostate tumor model. Cancer Immunol. Res., 202, canimm.0637.2020. doi: 10.1158/2326-6066. CIR-20-0637.

2. Li F., Chen Y., Pang M., Yang P., Jing H.. Immune checkpoint inhibitors and cellular treatment for lymphoma immunotherapy. Clin. Exp. Immunol., 2021. doi: 10.1111/cei.13592.

3. Sennikov S.V., Alshevskaya A.A., Zhukova J., Belomestnova I., Karaulov A.V., Lopatnikova J.A. Expression density of receptors as a potent regulator of cell function and property in health and pathology. Int. Arch. Allergy Immunol., 2019, Vol. 178, no. 2, pp. 182-191.

4. Shou J., Zhang Z., Lai Y., Chen Z., Huang J. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: a systematic review and meta-analysis. BMC Cancer, 2016, Vol. 16, no. 1, 687. doi: 10.1186/s12885-016-2732-0.