Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

Abstract

Summary The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

“…NLRC4 ) . Importantly, using recently published transcriptomic data sets of blood monocytes from an independent cohort of BC, we confirmed that genes such as HBEGF , CD83 , CD69 , ID2 and HIF1A were statistically down‐regulated, while DDX58 , NLRC4 , TNFSF10 , CXC3R1 and CCR2 genes were statistically up‐regulated in patient monocytes compared to HD monocytes (Figure e). Altogether, these findings revealed important differences in the transcriptional profiles of BC patient and HD monocytes, strongly suggesting that tumor development can act systemically, modifying the transcriptional profile of circulating monocytes.…”

“…We performed single‐sample scoring analysis to evaluate the sensitive and refractory signatures, as well as the hallmark signatures for IFN‐α response and OXPHOS identified in Figure a. We demonstrated in an independent cohort of BC patients that, unlike the refractory signature, the sensitive signature score was significantly higher ( P = 0.0037) in monocytes with a high IFN signature score (Figure f). This sensitive signature score was also more significantly enriched in monocytes expressing a high OXPHOS score, compared to the refractory signature score, which was at the limit of significance when comparing monocytes with high versus low OXPHOS status in the Cassetta cohort ( P = 0.045; Figure f).…”

“…(d) Bar plot of the top 100 DEGs between HD and patient monocytes (log 2 fold change ≤ 0.58 and FDR ≤ 0.05). (e) Normalised expression of selected genes from our study in an independent cohort of BC from Cassetta et al …”

“…In this context, we have previously shown that circulating monocytes from breast cancer (BC) patients fail to differentiate into functional dendritic cells (DCs) and present an altered cytokine profile in response to in vitro stimulation . Furthermore, other recent studies also highlighted the altered profile of circulating myeloid cells in both human and mouse cancer‐bearing hosts, strongly suggesting a systemic role for tumors in skewing monocytes.…”

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

“…Although elevated M‐CSF serum levels have been reported in HL patients, and HL cells were found to be M‐CSF‐positive by immunohistochemistry, the measured M‐CSF amounts in the lymphoma‐CM in vitro and the differences in Mφ counts and phenotype indicate the involvement of additional factors during HL‐specific Mφ differentiation (Casagrande et al , ; Kowalska et al , ; Zheng et al , ). Recently, an autoregulatory loop between TAMs and breast cancer cells has been reported (Cassetta et al , ). It might be interesting to test whether described factors such as tumor necrosis factor alpha, SIGLEC1 and CCL8, which is self‐reinforcing through the production of M‐CSF, also participate in the interaction of HL cells with Mφ.…”