The Immune Microenvironment in Hormone Receptor–Positive Breast Cancer Before and After Preoperative Chemotherapy

Abstract

Purpose: Hormone receptor-positive/HER2-negative (HR þ /HER2 À ) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR þ /HER2 À breast tumors.Experimental Design: HR þ /HER2 À breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8 þ cells, CD68 þ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.Results: Ninety-six patients were analyzed from two cohorts (n ¼ 55, Dana-Farber cohort; n ¼ 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissuebased lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBER-SORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N ¼ 302). In paired pre-/postchemotherapy samples, sTIL and CD8 þ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy.Conclusions: The immune microenvironment of HR þ / HER2 À tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophagetargeting therapy is warranted.

Accelerated Partial Breast Irradiation: Macrophage Polarisation Shift Classification Identifies High-Risk Tumours in Early Hormone Receptor-Positive Breast Cancer

“…Additional non-radiation based treatment might be appropriate, as there is evidence of macrophage induced radio-resistance after TAM cancer cell fusion [35,36]. Waks et al also reported a possible role for M2-like macrophages in chemo-resistance in HR+ breast cancer [37]. These results demonstrate that macrophage polarisation targeting therapies like CSF inhibitors might become valuable therapeutic options for breast cancer treatment [38,39].…”

Prognostic Significance of Tumor-infiltrating Lymphocytes in Premenopausal, Luminal Breast Cancer Treated with Adjuvant Endocrine Therapy

“…Some study reported that the presence of intratumoral CD8 + lymphocytes was not associated with breast cancer-speci c survival in ER + breast tumors (7). Another study found that higher levels of CD8 + T cells were associated with favorable responses to neoadjuvant chemotherapy, but not with improved outcomes (15). In contrast, two studies revealed that LBC regardless of the HER2 status with high CD8 + T-cells in ltration were associated with unfavorable outcome (16,26), which are contrary to our results.…”

“…However, studies on the potential clinical relevance of TILs in LBC have generated mixed results. Some studies reportied that TILs or CD8 + T-cells had no prognostic value in LBC (1,7), whereas two studies reported that high TILs conferred a signi cantly higher likelihood of pCR in LBC patients, although they did not signi cantly improve long-term outcomes (14,15). Similarly, another study showed that a high CD8 + T-cell exhaustion signature score, indicating a low CD8 + T-cell level, was associated with worse disease-free survival (DFS) in LBC patients regardless of HER2 status (16).…”

Pan-Cancer Analysis of Radiotherapy Benefits and Immune Infiltration in Multiple Human Cancers

“…Cancer cells often express programmed cell death-ligand 1 (PD-L1) and subsequently induce T-cell apoptosis, and PD-L1 status is an important factor in the prediction of the clinical outcome following RT in BRCA patients [22]. However, a comprehensive analysis of the correlation of RT outcome with immune infiltration has not yet been reported [23].…”