The prognostic and predictive role of tumor-infiltrating lymphocytes (FoxP3 + and CD8 +) and tumor-associated macrophages in early HER2 + breast cancer

Abstract

Purpose In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody trastuzumab and the patient’s outcome. In this HER2 + patient cohort, our aim was to study the numbers of FoxP3 + regulatory TILs and CD8 + cytotoxic TILs, their correlations with CD68 + and CD163 + TAMs, and the prognostic and predictive value of the studied factors. Methods We evaluated 139 non-metastatic HER2 + breast cancer patients operated between 2001 and 2008. The FoxP3+TIL count (FoxP3+TILs) was assessed using the hotspot method, and the CD8 + TIL count (CD8+mTILs) utilizing a digital image analysis from invasive margin areas. The ratios between CD8+mTILs and FoxP3+TILs as well as CD8+mTILs and TAMs were calculated. Results FoxP3 + TILs and CD8 + mTILs correlated positively with each other (p<0.001). FoxP3+TILs had a positive correlation with CD68+and CD163+TAMs (p≤0.038), while CD8 + mTILs correlated only with CD68+TAMs (p<0.001). In the HER2 + and hormone receptor-positive Luminal B subgroup, high numbers of FoxP3+TILs were associated with shorter disease-free survival (DFS) (54% vs. 79%, p = 0.040). The benefit from adjuvant trastuzumab was extremely significant among patients with a high CD8 + mTILs/CD68 + TAMs ratio, with overall survival (OS) 84% vs. 33% (p = 0.003) and breast cancer-specific survival (BCSS) 88% vs. 48% (p = 0.009) among patients treated with or without trastuzumab, respectively. Conclusion In the HER2 + Luminal B subgroup, high FoxP3 + TILs were associated with shorter DFS. A high CD8 + mTILs/CD68 + TAMs ratio seems to associate with impressive efficacy of trastuzumab.

High Numbers of CD163+ Tumor-Associated Macrophages Predict Poor Prognosis in HER2+ Breast Cancer

“…Indeed, there are ongoing phase 1-2 trials investigating treatments combining anti-HER2 agents with some forms of TAM-directed therapy in HER2+ carcinomas, e.g., HER2-targeted immune-stimulating antibody conjugate locally activating the innate immune system [40] and anti-HER2 CAR macrophage therapy [41]. Nevertheless, there is also evidence suggesting that the efficacy of trastuzumab may be affected more by interactions between different types of immune cells, e.g., the ratios of TILs and TAMs, rather than by the numbers of a single immune cell type on its own [42,43], which highlights the complexity of the immune responses present in the TME.…”

Nano-Pulse Treatment Overcomes the Immunosuppressive Tumor Microenvironment to Elicit In Situ Vaccination Protection against Breast Cancer

“…A significant discovery in this study is that NPT exhibits selective cytotoxicity towards Tregs while sparing effector CD4 + and CD8 + T cells. Treg predominance suggests worse outcomes for many cancer types, including breast, while a high CD8 + or CD8 + /Treg ratio is associated with a better prognosis [ 29 , 30 , 31 , 32 ]. A significant knockdown of Tregs and an increase in effector CD4 + and CD8 + /Treg ratios would favor the induction of antitumor immunity.…”

Prognostic Significance of CD163+ and/or CD206+ Tumor-Associated Macrophages Is Linked to Their Spatial Distribution and Tumor-Infiltrating Lymphocytes in Breast Cancer

“…TNBC with high TAMs (CD68/CD163) and low TILs, but not those with high TILs, was associated with poor patient survival [ 17 ]. HER2+ breast cancers with a high CD8-TIL-to-CD68-TAM ratio derived more benefit from anti-HER2 treatment [ 18 ]. Additionally, the spatial localization of TAMs could also affect the prognosis.…”