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Associations of tils components CD8, CD4, PD-L1, CTLA4 and FOXP3 in triple negative breast carcinoma with the clinicopathological prognostic factors

Background:Triple-negative breast cancer (TNBC) has the worst prognosis and the highest immunogenic potential of all breast cancer subtypes. The tumour microenvironment (TME) of TNBC consists mostly of tumour-infiltrating lymphocytes (TILs), tumour-associated macrophages and dendritic cells. TILs are involved in host immunity against tumour cells through the activation of tumour-specific CD8+ cytotoxic T cells. However, there are opposing data about the prognostic value of TILs in TNBC. Programmed cell death receptor ligand 1 (PD-L1) from immune or tumour cells binding programmed cell death receptor 1 (PD-1) disable the effector role of CD8 T cells. Therefore, antibodies that block the target in the PD-1 signalling pathway elicit a stronger immune response. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) mediates immunosuppression and it is expressed in tumours on infiltrating Tregs, activated CD4+ T cells, exhausted T cells and tumour cells. In tumours with high TILs, PD-L1 and CTLA-4 blockades are more effective. Methods:We have performed a comprehensive IHC analysis of all major TIL components (CD8, CD4, FOXP3 Tregs) as well as inhibitory molecules PD-L1 and CTLA4) in a superficial (invasive tumour front, ITF) and deep tumour layer of TNBC, and compared it with established clinicopathological and prognostic parameters. Clinical data and surgical tissue samples from 68 TNBC patients who underwent initial surgery were included in the analysis and 36 control samples from benign breast tissue biopsies. Results:Several statistically significant associations between the TILs status of TNBC patients and the established prognostic factors were observed. In the ITF, the proportion of TILs and CD8+T cells were increasing toward second pathological T status (pT2), and decreasing thereafter toward higher pT status (P=0.017, P=0.021, Chi-square test). Similar trends for both variables were observed in association with anatomic (P=0.057, P=0.050, Chi- square test) and prognostic (P=0.059, P=0.048, Chi-square test) stages of the disease. Furthermore, the increase of CD8+T cells at ITF was statistically correlated with the increased expression of PDL-1, CTLA-4, FOXP3 and CD4+T cells (N=65, rho 0.31, P=0.011 ; N=65, rho 0.40, P<0.001 ; N=61, rho 0.32, P=0.012 ; N=66, rho 0.40, P<0.001). Lib Oncol. 2022 ; 50(Suppl 1):85–156 92 Conclusion: The TILs dynamic in relation to the stage of the disease, observed in the ITF, suggeststhat commencing checkpoint inhibitors immunotherapy in the earlier stages of the disease may be more effective, as compared to current clinical practice.

triple-negative breast cancer, tumour infiltrating lymphocytes, immunohistochemistry

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