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Clinical significance of TILs components in triple negative breast carcinoma

Goals: Tumour infiltrating lymphocytes (TILs) have recently emerged as promising new biomarkers and specific therapeutic targets in triple negative breast cancer (TNBC). However, their predictive and prognostic value is not yet fully understood. The aim of this study was the immunohistochemical (IHC) characterization of TILs in surgical biopsy specimens from TNBC patients. Methods: Clinical data and surgical tissue specimens from 68 TNBC patients who underwent the upfront surgery were included in the present analysis, as well as 36 control samples from benign breast tissue biopsies. A comprehensive IHC analysis of all significant TILs components (CD8, CD4, FOXP3, CD68 and CD11c) and immunosuppressive markers PDL-11 and CTLA4 at the invasive tumour front (ITF) and in the tumour centre (TC) was performed. Furthermore, their intercorrelations were analysed and their associations with stablished prognostic parameters and patients’ survival outcomes were tested. Results: TILs and CD8+T cell proportions are increasing toward pT2 and decreasing toward higher pT stages (P = 0.017, P = 0.21, Chi-square test). TILs density at ITF was statistically related to the expression of both CD8+ (N = 65, rho 0.56, p < 0.001, Spearman’s rank correlation) and CD4+ (N = 65, rho 0.50, p < 0.001, Spearman’s rank correlation) T cells. However, the expression of PDL-1, CTLA4 and FOXP3 was related to CD8+ T cell infiltration as well (N = 65, rho 0.31, P = 0.011 ; N = 65, rho 0.40, P < 0.001 ; N = 61, rho 0.32, P = 0.012, Spearman’s rank correlation). In the TC, TILs density was related only to the CD4+T cell infiltration (N = 65, rho 0.50, p < 0.001, Spearman’s rank correlation) and to the expression of PDL-1 and CTLA-4 (N = 66, rho 0.39, P = 0.001 ; N = 65, rho 0.46, p < 0.001, Spearman’s rank correlation). X-tile analysis was performed to determine the cut-off values, required for the TILs components’ prognostic value analysis. Following Cox regression multivariate analysis prognostic significance was confirmed for CD4 (cut-off 25%, P = 0.043, RR 2.36, HR95% 1, 03–5, 41) and PDL-1 (cut-off 5%, P < 0.001, RR 7.83, HR95% 2.32– 26.39) expression at ITF. Conclusion(s): Herein observed TILs dynamic and TILs composition suggest that commencing checkpoint inhibitors immunotherapy at the pT2 stage may be the most effective strategy. Routine determination of CD4+T cells and PDL-1 expression at the ITF may be of added value in deciding treatment escalation and de-escalation strategies in TNBC patients.

Triple-negative breast cancer Tumor infiltrating lymphocytes, Immunohistochemistry Prognosi

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