Immune-Activated Regional Lymph Nodes Predict Favorable Survival in Early-Stage Triple-Negative Breast Cancer

Abstract

Immune response and immunotherapy play important roles in triple-negative breast cancer (TNBC). However, it is difficult to judge whether cancer is “immune-inactivated” or “immune-activated” by the carcinoma itself. The immune reaction of the microenvironment or the host to the tumor might be more informative. We assumed that clinically enlarged but pathologically negative regional lymph nodes served as an indicator for early immune response to tumors. First, we identified women with pN0 breast cancer disease from the current Surveillance, Epidemiology, and End Results database, and we compared the cN1 patients of breast cancer-specific survival (BCSS) with cN0 patients. Then, we extracted total RNA from 36 paired large (defined as minimum diameter more than 15 mm in size) and small lymph nodes (defined as maximum diameter less than 5 mm in size) from 12 TNBC, 12 HER2-enriched, and 12 luminal-like patients and performed RNA sequencing to explore the gene expression and cellular landscape of large nodes compared to small ones. Among 692 women with pathologically confirmed node-negative disease, cN1 patients unexpectedly had a better BCSS compared with cN0 in TNBC (adjusted hazard ratio 0.148, 95% CI, 0.040–0.546, P = 0.004) but not in other subtypes. Further transcriptome sequencing of 12 paired enlarged and small negative nodes from TNBC patients revealed that increased immune activation signaling (e.g., interferon-gamma response pathways) and abundant immune cells (activated dendritic cells, CD4+ and CD8+ T-cells) were more frequently observed in enlarged nodes. Our data implied that early immune activation in regional lymph nodes in TNBC might affect survival.

A Novel IGLC2 Gene Linked With Prognosis of Triple-Negative Breast Cancer

“…However, the definition of "PD-L1-positive" population in clinical practice remains challenging (69). In addition, assessing whether a cancer is "immune activated" or "immune inactivated" is difficult (70). Therefore, finding new molecular biomarkers for the prediction immunotherapy response for TNBC is an urgent issue.…”

“…TNBC is the subtype of BCs most related to TIL infiltration and PD-1/PD-L1 expression (70). Among the TNBC subtypes, BLIA is enriched in immune-response genes, immune activated, and can benefit the most from immune checkpoint inhibitor treatment (69).…”

Local and systemic therapy may be safely de-escalated in elderly breast cancer patients in China: A retrospective cohort study

“…compared the outcomes of patients with cN0 and cN1 in preoperative assessment among 692 pN0 cases, and BCSS of cN1 patients was unexpectedly significantly longer than cN0 ones in TNBC. Using RNA sequencing, they found that enlarged ALNs in clinical imaging had higher expression of immune-related genes, such as IL21 , CCL17 , AOC1 , APOC2 , and NCCRP1 , and more abundant immune cells, such as dendritic cells, CD4+ T cells, and CD8+ T cells ( 36 ). Increased anti-tumor immunity improved survival, which partly explained our findings.…”

Leveraging the Dynamic Immune Environment Triad in Patients with Breast Cancer: Tumour, Lymph Node, and Peripheral Blood

“…Increased numbers of T and B cells in sentinel LNs [ 52 ] have been associated with longer DFS across different breast cancer subtypes irrespective of their nodal status, as are increased levels of axillary node CD4+ T cells and DC populations in LN-positive breast cancer patients [ 44 , 52 ]. Patients with enlarged LNs without metastatic involvement (indicative of an active immune response) experience longer breast-cancer-specific-survival [ 56 ]. Topically, swollen LNs are an unanticipated side effect of the immune reaction engendered by the COVID-19 vaccine which has been complicating breast cancer screenings.…”