Abstract
The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC.
Highlights
The development of novel therapeutic agents has significantly improved the survival rates of patients with breast cancer (BC), nearly 20–30% of those with early disease will relapse and die from their disease [1,2]
The expression of CD47 and progressive disease (PD)-L1 was evaluated in three human BC cell lines—SKBR-3, MCF-7, and MDA.MB.231—representing HER2-positive, luminal, and basal-like BC subtypes, respectively
Our results suggest that de novo metastatic BC may present an increased potential for immune escape compared to recurrent disease or alternatively, prior systemic treatment for early BC may have selected circulating tumor cells (CTCs) subsets bearing different immune escape properties
Summary
The development of novel therapeutic agents has significantly improved the survival rates of patients with breast cancer (BC), nearly 20–30% of those with early disease will relapse and die from their disease [1,2]. According to the theory of cancer immunosurveillance, the immune system has an important role in the elimination of cancer cells, as well as in the maintenance. Cancer cells exploit different mechanisms of immune evasion which enable them to grow and metastasize [3]. Immune cells of both the adaptive and innate immune system are involved in cancer immunosurveillance [5]. CD47 expression on primary breast tumors has been associated with lymph node metastases and poor patient outcomes [9]
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