Comparison of the tumor immune microenvironment phenotypes in different breast cancers after neoadjuvant therapy.

Neoadjuvant therapy (NAT) treats early-stage breast cancers, especially triple-negative breast cancers (TNBCs). NAT improves pathological complete response (pCR) rates for different breast cancer patients. Recently, immune checkpoint inhibitors that target programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) in combination with NAT have shown antitumor activity in patients with early breast cancer. However, the tumor immune microenvironment (TME) in different subtypes of breast cancers, like TNBC, hormone receptor-positive (HR+), and human epidermal growth factor receptor 2 amplified (HER2+) and its changes by NAT remain to be fully characterized. We analyzed pre-NAT tumor biopsies from TNBC (n = 27), HR+ (n = 24), and HER2+ (n = 30) breast cancer patients who received NAT, followed by surgery. The different immune makers (PD-1, PD-L1, CD3, and CD8) of tumor-infiltrating lymphocytes (TILs) were identified with immunofluorescence-based microenvironment analysis. TILs within cancer parenchyma (iTILs) and in cancer stroma (sTILs) were counted separately. We found that PD-L1+ cells in tumor and stroma were significantly higher in TNBC patients than in others. PD-L1+ sTILs were significantly higher in pCR than in non-pCR patients of all the subtypes. The infiltration scores of B-cell memory, T-cell CD4+ memory activated, T-cell follicular helper, and Macrophage M0 and M1 were relatively higher in TNBC patients, indicating immunoreactive TME in TNBC. Analysis of TCGA-BRCA RNA-seq indicated that PD-L1 was highly expressed in TNBC patients compared with HR+ and HER2+ patients. Higher PD-L1 expression in TNBC patients was associated with significantly longer overall survival (OS). Our results demonstrated that PD-L1 expression level of iTILs and sTILs is highest in TNBC among breast cancers. TNBC patients had significantly different immunoreactive TME compared with HR+ and HER2+ patients, suggesting potentially favorable outcomes for immunotherapy in these patients. Also, PD-L1+ could be a powerful predictor of pCR in TNBC patients after NAT.

Han M ，Li J ，Wu S ，Wu C ，Yu Y ，Liu Y ... -  《Cancer Medicine》

The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC).

Tomioka N ，Azuma M ，Ikarashi M ，Yamamoto M ，Sato M ，Watanabe KI ，Yamashiro K ，Takahashi M ... -  《-》

Immune microenvironment changes induced by neoadjuvant chemotherapy in triple-negative breast cancers: the MIMOSA-1 study.

Sarradin V ，Lusque A ，Filleron T ，Dalenc F ，Franchet C ... -  《-》

Integration of tumour infiltrating lymphocytes, programmed cell-death ligand-1, CD8 and FOXP3 in prognostic models for triple-negative breast cancer: Analysis of 244 stage I-III patients treated with standard therapy.

Tumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs. Primary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin-eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology. TILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P < 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χ2 4.60, P = 0.032 (in a model including classic factors and TILs 10% increments) and likelihood ratio χ2 6.50, P = 0.011 (in a model including classic factors and TILs >30% versus <30%). In the subset of patients treated with neoadjuvant chemotherapy, FOXP3 provided further prognostic information beyond classic factors, TILs and pathological complete response (pCR) (likelihood ratio χ2 5.01, P = 0.025). For patients who did not achieve a pCR, the expression of CD8 and PD-L1 was significantly increased from baseline to residual disease. Beyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting.

Dieci MV ，Tsvetkova V ，Griguolo G ，Miglietta F ，Tasca G ，Giorgi CA ，Cumerlato E ，Massa D ，Lo Mele M ，Orvieto E ，Guarneri V ，Conte P ... -  《-》

Tumor Microenvironment in Male Breast Carcinoma with Emphasis on Tumor Infiltrating Lymphocytes and PD-L1 Expression.

Brcic I ，Kluba AM ，Godschachner TM ，Suppan C ，Regitnig P ，Dandachi N ，Lax SF ，Balić M ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》