Predictive factors of the tumor immunological microenvironment for long‐term follow‐up in early stage breast cancer

Abstract

The aim of this research was to investigate the correlation of immunologic factors in the tumor environment of breast cancer, using immunohistological staining to evaluate the expression of programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1), phosphatase and tensin homolog (PTEN), tumor infiltrating lymphocytes (TILs), and macrophages, and to analyze the association between the immunologic factors and clinical outcome for patients with early stage breast cancer (EBC). A total of 97 EBC patients who underwent standard surgery were investigated. Expression of PD‐1/PD‐L1 and PTEN and the density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages were evaluated by immunohistochemical analysis. The association between the immunologic factors and clinical outcome was statistically analyzed. The density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages and non‐expression of PTEN was significantly higher in cases of triple negative breast cancer. CD8+ TIL density and CD8+/PD‐L1+ expression were predictive factors for disease‐free survival and overall survival (OS). Human epidermal growth factor 2 (HER2)‐positive patients with PTEN expression and luminal/HER2‐negative patients without PD‐L1 expression had significantly longer OS compared to patients without PTEN expression (P = 0.049) and with PD‐L1 expression (P = 0.036), respectively. Furthermore, patients with PD‐L1+/CD8+ expression had worse median progression‐free survival (P = 0.022) and median OS (P = 0.037) compared with patients without PD‐L1+/CD8+ expression. The CD3+ TILs, CD8+ TILs, and CD163+ macrophages were shown to infiltrate the tumor area of EBC. In particular, triple negative breast cancer had a higher rate of TIL infiltration within the tumor environment. Expression of PTEN and lack of PD‐L1 expression were associated with favorable survival in HER2‐positive and luminal/HER2‐negative EBC patients, respectively. The PD‐L1 expression combined with CD8+ density was significantly associated with an aggressive clinical outcome.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…PD‐L1 expression evaluated by IHC on untreated primary BC has been associated with both better and poorer clinical outcome. In particular, several authors reported poorer disease‐free survival (DFS)/recurrence‐free survival (RFS) and/or overall survival (OS) in cases of higher PD‐L1 expression on primary BC , especially in the TN subtype . These results seems to be consistent with the previously mentioned correlation between PD‐L1 expression and unfavorable clinicopathological BC features, thus possibly indicating that PD‐L1 expression may be part of the immune evasion process taking place in the context of tumor microenvironment .…”

Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone?

“…Recently, another study revealed that [88] patients with high density of CD8+ TILs had a longer disease-free survival (DFS), and CD8+/PD-L1 was a positive prognostic factor associated with longer OS in patients with luminal/HER-EBC . [89] Recently, di erent studies reported the presence of PD-L1 also in ff breast cancer suggesting its role as a new therapeutic target mostly in HER+ tumors, in which are found the major levels of PDL-1 expression [90 92] -. Indeed, the expression of PD-L1 on activated T cells maintained an immunosuppressive tumor microenvironment, o ering the possibility ff to use monoclonal antibodies targeting PD-L1 and its receptor PD1 which are able to reactivate the antitumor immune response .…”

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…PD-1/PD-L1 expression in metastatic tumors was correlated with poor prognosis, whereas no relation to clinicopathological features was noted in primary tumors [109]. In essence, it can be seen from literature that high PD-L1 expression combined with an increase in T regulatory cells (Tregs) and a decrease of TILs are associated with poor survival [22,102,107,110]. However, high PD-1/PD-L1 expression along with a higher number of TILs in the tumor microenvironment is associated with improved OS (overall survival) and/or DFS (disease free survival) [24,111,112].…”

“…The FinHER trial demonstrated the link between improved response to trastuzumab and higher levels of TILs among HER2 + BC patients [125]. It showed that in the case of HER2 + tumors which are highly proliferative, the presence of TILs in the tumor microenvironment is a predictive biomarker for favorable responses to trastuzumab treatment [102,110,126,127]. As mentioned in [102,117,127] the experimental analysis on HER2 + patients suggests that CD8 + T cell-mediated cytotoxicity and PD-L1 expression together may predict improved outcome in HER2 + BC patients under combined chemotherapy and HER2-targeted therapy [102].…”