Is it TIME for the clinical stratification of HR+/HER2- breast cancer?

Background & Objectives: Tumour immune microenvironment (TIME) plays a pivotal role in the prognosis and therapeutic response in triple-negative and HER2+ breast cancer (BC). Our study aimed to characterize TIME cellular composition of HR+/HER2- BC to gain insight into tumour biology. Methods: Tissue Microarrays from 70 HR+/HER2- BC patients have been created. Imaging analysis ( HALO®) was used to assess the immunohistochemical expression of immune markers (CD3, CD20, CD4, CD8, FOXP3, CD68/KP1, CD163, iNOS). Statistical analysis was performed using GraphPad Prism Software. The study was approved by the local Ethical Committee and was partially funded by Gilead Fellowship Program 2023. Results: Both CD4+ and CD8+ tumour-infiltrating lymphocytes (TILs) were higher in tumour stroma than in the normal counterpart (P=0.0087 and P=0.0014, respectively). This was particularly significant for the FOXP3+ subpopulation, which include regulatory T cells (Treg, CD4+/ FOXP3+) and activated CD8+ T cells (CD8+/FOXP3+) (P=0.0007). Interestingly, the tumour stroma was also enriched in Th1 TILs (CD4+/ FOXP3-) (P=0.0096). In terms of prognosis, the metastatic tumours had less CD4+/FOXP3- TILs than the non-metastatic ones (P=0.0045). Together, tumour associated macrophages (TAMs) were polarized into M1 (pro-tumoral) and M2 (anti-tumoral) phenotypes. Conclusion: These data suggest a complex interplay between immune cells in HR+/HER2- BC: while the presence of CD4+ and CD8+ TILs may indicate an active immune response, the enrichment of Tregs, activated CD8+ T cells and TAMs suggests a potentially dysfunctional immune response. Intriguingly, the lower levels of Th1 TILs in metastatic tumours imply that the immune environment may be less capable of mounting an effective response, and their depletion could be a marker of poor prognosis.