The presence of PD-1 positive tumor infiltrating lymphocytes in triple negative breast cancers is associated with a favorable outcome of disease

Abstract

Triple negative breast cancer patients have a poor course of disease not least because of limited treatment options however immunotherapy by targeting the PD-1/PD-L1 checkpoint system is a promising strategy to improve the outcome. Here we systematically investigated the expression of PD-1 on tumor infiltrating lymphocytes and PD-L1 on both tumor and infiltrated immune cells. Moreover, the PD-L1 gene status in tumor cells was assessed.103 tissue microarray samples derived from triple negative breast cancer specimens were immunohistochemically stained against PD-1 and PD-L1. Dual marker fluorescence in-situ hybridization was applied to the PD-L1 gene and centromere region of chromosome 9. The disease free and overall survival rates were determined as a function of the PD-1/PD-L1 status.A slight gain of the PD-L1 gene region was found in 55% of all samples but an elevated PD-L1/cen9 ratio was rather rare (7%). An increased gene dose is not associated with an enhanced protein expression and the PD-L1 expression only weakly correlates with the amount of immune cell infiltration. Instead, we found an association of PD-L1 expression on tumor and immune cells, respectively. Notably, the PD-1 expression on immune cells is associated with a favorable disease free and overall survival. PD-1 expression indicates an enhanced immunological anti-tumor activity and represents a favorable prognostic impact. A deeper understanding of factors that affect the regulation and function of the PD-1/PD-L1 system is required to establish predictive variables and to utilize the system for therapeutic intervention of triple negative breast cancer patients.

Multi-panel immunofluorescence analysis of tumor infiltrating lymphocytes in triple negative breast cancer: Evolution of tumor immune profiles and patient prognosis

“…Robust levels of stromal TILs have been associated with improved response to neoadjuvant therapy with increased pathological complete responses (pCR) in TNBC [5]. Higher TILs is also associated with improved disease-free and overall survival rates in TNBC [13,[23][24][25]. Besides TILs, increased programmed cell death protein 1 ligand (PD-L1) [26] expression on the surface of tumor, and increased tumor mutation burden represent potential predictive markers for immune checkpoint inhibitor response.…”

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

“…Tumor‐infiltrating immune cells (TIICs), whose function and composition subtly altered according to the immune status of the host, have been reported to be effectively targeted by drugs and to correlate with the clinical outcome . Mechanism studies confirmed that between TIICs and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has a dual role by supporting both host defense and tumor progression .…”

“…Tumor-infiltrating immune cells (TIICs), whose function and composition subtly altered according to the immune status of the host, have been reported to be effectively targeted by drugs and to correlate with the clinical outcome. 2,8,9 Mechanism studies confirmed that between TIICs and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has a dual role by supporting both host defense and tumor progression. 10 As an immunosensitive tumor, CRC infiltrated by a heterogeneous collection of TIICs, including T cells, dendritic cells, macrophages, neutrophils, and mast cells, and it has been frequently reported that the type, density, and location of TIICs within CRC present with great prognostic value.…”

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: What is the Evidence?

“…These divergent results in survival outcomes might not necessarily be contradictory but rather highlight different stages of a complex and intricate process. PD-L1 and PD-1 expression might be a dynamic process affected by the surrounding microenvironment involving different signaling pathways, transcriptional factors, microRNAs and epigenetic factors [42,43]. Interestingly Brackhoff et al [42] demonstrated that in TNBC, PD-L1 gene copies may be amplified, fall in the normal range or even below the average copy numbers in normal breast tissue, and PD-L1 gene expression did not correlate with PD-L1 protein expression.…”

“…PD-L1 and PD-1 expression might be a dynamic process affected by the surrounding microenvironment involving different signaling pathways, transcriptional factors, microRNAs and epigenetic factors [42,43]. Interestingly Brackhoff et al [42] demonstrated that in TNBC, PD-L1 gene copies may be amplified, fall in the normal range or even below the average copy numbers in normal breast tissue, and PD-L1 gene expression did not correlate with PD-L1 protein expression. The study also demonstrated a direct correlation between PD-1 expression on TILs and PD-L1 expression on tumor cells; PD-1 expression on TILs was found to be the strongest prognostic factor of a favorable survival outcome [42].…”