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T cell proliferation and activation in response to TaMs.: CFSE-labeled T cells were stimulated in vitro with anti-CD3 and anti-CD28 plus differentiated macrophages (Ctrl), PC-TaMs or CRC-TaMs for 72 h or left unstimulated. Proliferation of T cells was analysed by flow cytometry. (a) Individual percentages of divided cells in the second to fourth cell division. Each dot represents one individual and one separate experiment and horizontal bars indicate mean values. (b) Representative CFSE histograms with T cells co-cultured with TaMs induced by conditioned medium from PC cells 22Rv1 (22Rv1-TaM) and VCaP (VCaP-TaM), or CRC cells Sw480 (Sw480-TaM) and Caco2 (Caco2-TaM). The bold line represents T cells stimulated by macrophages and the filled line unstimulated control. Arrow indicates cells in the fourth round of cell division. (c) Expression of T cell activation markers CD69 and CD25 after co-culture with PC-TaMs or CRC-TaMs, as detected by immunostaining and flow cytometry. The population of Tregs is defined as CD3+CD4+CD25+CD127− cells. Shown are percentage positive cells ± SD from three independent experiments. Significant P-values are indicated.
Source publication
Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2 +) and immunosuppressive M2 macrophages (CD163 +) was evaluated in a cohort of 234 PC pat...
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Citations
... MACRO-M2 CD68 + TAMs correlated with a higher TNM stage, peritumoral lymphatic vessel density (LVD), and LN metastasis CD163 + TAMs accumulation is strongly associated with reduced progression-free survival (PFS) CD204 + TAMs correlated with tumor differentiation, pathologic stage, T status, nodal involvement, lymphatic permeation, vessel invasion, and pleural invasion MACRO + TAMs contribute to an immunosuppressive mechanism protecting cancer cells (Almatroodi et al. 2016;Rakaee et al. 2019;Zhang et al. 2011;Yusen et al. 2018;Li et al. 2018;Yang et al. 2015;La Fleur et al. 2018) Ovarian cancer CD68-Pan macrophages CD80-M1 CD163-M2 CD68 + TAMs are significantly associated with lower OS CD163 + TAMs are negative predictors of PFS and OS (Lan et al. 2013;No et al. 2013;Yin et al. 2016) Prostate cancer CD68-Pan macrophages YKL40-M1 CD163-M2 CD68 + TAMs are associated with TNM clinical stage and are predictors of shorter CSS CD163 + TAMs are associated with a higher incidence of metastasis and a lower incidence of CSS (Lundholm et al. 2015;Takayama et al. 2009) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Background
Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME.
Methods
We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs.
Results
TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis.
Summary
Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
... The tumor microenvironment (TME) acts as a major barrier for the recruitment and activation of effector lymphocytes 16 . The composition and physical properties of the TME are regulated by secreted factors during tumor development, and the proteins secreted by cancer cells play pivotal roles in this regulation [17][18][19] . Thus, strategies targeting cancer cell-secreted factors can be exploited to not only inhibit cancer cell proliferation and metastasis but also maximize the benefit of immunomodulatory therapies. ...
Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8⁺ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8⁺ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.
... In addition, the loss of major histocompatibility complex (MHC) classes I and II, often observed in PCa, results in the reduced infiltration of cytotoxic T-cells into the tumor, and it has been shown to be one mechanism of immune evasion in mCRPC cell lines and clinical specimens [100][101][102]. Furthermore, the presence of tumor-associated macrophages (TAMs) is commonly associated with anti-inflammatory responses [103]. In addition to the immune cell-associated properties that pose challenges for immunotherapies, other PCa-specific features increase the difficulty of targeting the prostate TME as a therapeutic strategy. ...
Simple Summary
Prostate cancer is a prevalent cancer in men. Metastatic disease is initially responsive to androgen receptor signaling inhibition, but eventually resistance develops despite continuation of therapy. This resistance involves multiple adaptations in the cell but also to the tumor microenvironment, including epigenetic alterations. Epigenetic alterations change gene expression without DNA sequence modifications and play a key role as regulators of cell functions both in the tumor and the tumor microenvironment. Moreover, these epigenetic alterations highlight potential therapeutic targets. Targeting these epigenetic modifications could improve androgen receptor-targeted therapy and enhance anti-tumor immunity. In this review we discuss the role of epigenetics in prostate cancer, strategies to target them, and their impact on the tumor microenvironment, with the goal of identifying novel therapeutic avenues for advanced prostate cancer.
Abstract
Prostate cancer is the second most common cancer in men worldwide and is associated with high morbidity and mortality. Consequently, there is an urgent unmet need for novel treatment avenues. In addition to somatic genetic alterations, deviations in the epigenetic landscape of cancer cells and their tumor microenvironment (TME) are critical drivers of prostate cancer initiation and progression. Unlike genomic mutations, epigenetic modifications are potentially reversible. Therefore, the inhibition of aberrant epigenetic modifications represents an attractive and exciting novel treatment strategy for castration-resistant prostate cancer patients. Moreover, drugs targeting the epigenome also exhibit synergistic interactions with conventional therapeutics by directly enhancing their anti-tumorigenic properties by “priming” the tumor and tumor microenvironment to increase drug sensitivity. This review summarizes the major epigenetic alterations in prostate cancer and its TME, and their involvement in prostate tumorigenesis, and discusses the impact of epigenome-targeted therapies.
... M2 exert an immunosuppressive and pro-tumorigenic activity, and their main surface markers are CD206, CD163, and CD204 [42,[44][45][46]. Although this dichotomy has been acknowledged as an over-simplification, an imbalance between M1 and M2 in favor of M2 in the TME, appears to be associated with tumor growth, angiogenesis, and metastasis [42,47,48]. sEVs have been recognized not only as important mediators of communication among the various components of the TME [41], but also, when isolated from numerous cancer cell lines [49], including prostate [50][51][52], as modulators of macrophage polarization in vitro. ...
Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients’ plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as “adhesion competent”. Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer.
... Some studies show increased numbers of both M1 and M2 macrophages in tumor tissue compared to normal tissue [5]. However, another report suggests that in PCa, the majority of tumor-infiltrating macrophages are M2 macrophages [14]. This study also shows that high infiltration of M2 macrophages correlates with a worse prognosis. ...
Prostate cancer (PCa) is a low tumor mutational burden (TMB) cancer with a poor response to immunotherapy. Nonetheless, immunotherapy can be useful, especially in metastatic castration-resistant PCa (mCRPC). Increased cytotoxic T lymphocytes (CTLs) density is correlated with a shorter overall survival (OS), an early biochemical relapse, and a generally poor PCa prognosis. An increased number of CCR4+ regulatory T cells (CCR4 + Tregs) relates to a higher Gleason score or earlier progression. The same therapeutic options are available for renal transplant recipients (RTRs) as for the population, with a comparable functional and oncological outcome. Radical retropubic prostatectomy (RRP) is the most common method of radical treatment in RTRs. Brachytherapy and robot-assisted radical prostatectomy (RARP) seem to be promising therapies. Further studies are needed to assess the need for prostatectomy in low-risk patients before transplantation. The rate of adverse pathological features in RTRs does not seem to differ from those observed in the non-transplant population and the achieved cancer control seems comparable. The association between PCa and transplantation is not entirely clear. Some researchers indicate a possible association between a more frequent occurrence of PCa and a worse prognosis in advanced or metastatic PCa. However, others claim that the risk and survival prognosis is comparable to the non-transplant population.
... But a high infiltration by CD163 + cells was associated with a lower cancer-specific survival (p=0.002) when compared to a low infiltration. However, multivariate analyses adjusted for clinicopathological factors did not find any statistical correlation (44). In contrast, our results may have reached statistical significance given our selection of higher risk patients with more clinical events such as metastases and death related to PCa expected to occur. ...
Introduction
Prostate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.
Methods
Infiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.
Results
Positive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209⁺ and CD163⁺ cells were more abundant at the tumor margin. Higher CD209⁺/CD83⁺ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163⁺ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.
Conclusion
A higher level of infiltration of CD209⁺ immature DC and CD163⁺ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes.
... Generally, these hallmarks establish connections to activate PCa initiation, promotion, and metastasis, thereby leading to variable prognosis. Decreased M1/M2 ratios, reduced Th1 infiltration, and functionally inactivated T cells lead to poor prognosis in PCa [165]. Increased glucose uptake sustains hexosamine biosynthesis pathway-dependent O-GlcNAcylation to promote cancer spread and chemoresistance, whereas M2-like TAMs have the highest individual capacity to take up intertumoral glucose. ...
The distinct tumor microenvironment (TME) of prostate cancer (PCa), which promotes tumor proliferation and progression, consists of various stromal cells, immune cells, and a dense extracellular matrix (ECM). The understanding of the prostate TME extends to tertiary lymphoid structures (TLSs) and metastasis niches to provide a more concise comprehension of tumor metastasis. These constituents collectively structure the hallmarks of the pro-tumor TME, including immunosuppressive, acidic, and hypoxic niches, neuronal innervation, and metabolic rewiring. In combination with the knowledge of the tumor microenvironment and the advancement of emerging therapeutic technologies, several therapeutic strategies have been developed, and some of them have been tested in clinical trials. This review elaborates on PCa TME components, summarizes various TME-targeted therapies, and provides insights into PCa carcinogenesis, progression, and therapeutic strategies.
... [10][11][12][13][14][15] CD68 + CD163 + M2 macrophages and regulatory Tcells (Tregs) expressing transcription factor forkhead box subfamily 3 (FOXP3), on the other hand, are tumor cell supportive due to their ability to suppress the antitumor immune response, stimulating cell growth and healing processes as well as impairing treatment effects and prognosis. [16][17][18][19][20][21][22][23][24] The immunosuppressive function of FOXP3 + Tregs is mediated through their expression of immune-checkpoint inhibitors (ICI). Several ICI blockers have been used to treat different cancers, as have drugs that reduce the number of M2 macrophages, but unfortunately so far with little success in PCa when used as a single treatment. ...
... It has previously been shown that the majority of the TAM present in PCa tissue is of an M2 phenotype. 18,19,32 After neoadjuvant ADT combined with RT, a significant increased infiltration of CD68 + TAM was demonstrated using the mIHC method. Standard IHC staining showed that 75% of untreated biopsies and 92% of cases treated with neoadjuvant ADT combined with RT had a high infiltration of CD163 + cells. ...
... Previous studies have demonstrated the same correlations, and this further supports the reliability of the mIHC method used in this study. 18,19 Another advantage of our study is that investigating five different immune cells simultaneously in the same tissue section saved working hours and valuable tissue material. The digital approach also allowed us to control for unspecific binding, necrotic tissue, and irrelevant areas when calculating cells/mm 2 , as well as making it possible to identify cells stained with multiple markers. ...
Objectives:
Androgen deprivation therapy (ADT) has long been a cornerstone in treatment of advanced prostate cancer (PCa), and is known to improve the results of radiotherapy (RT) for high-risk disease. The purpose of our study was to use a multiplexed immunohistochemical (mIHC) approach to investigate the infiltration of immune cells in PCa tissue after eight weeks of ADT and/or RT with 10 Gy.
Methods:
From a cohort of 48 patients divided into two treatment arms, we obtained biopsies before and after treatment and used a mIHC method with multispectral imaging to analyze the infiltration of immune cells in tumor stroma and tumor epithelium, focusing on areas with high infiltration.
Results:
Tumor stroma showed a significantly higher infiltration of immune cells compared to tumor epithelium. The most prominent immune cells were CD20+ B-lymphocytes, followed by CD68+ macrophages, CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and T-bet+ Th1-cells. Neoadjuvant ADT followed by RT significantly increased the infiltration of all five immune cells. Numbers of Th1-cells and Tregs significantly increased after single treatment with ADT or RT. In addition, ADT alone increased the number of cytotoxic T-cells and RT increased the number of B-cells.
Conclusions:
Neoadjuvant ADT in combination with RT results in a higher inflammatory response compared to RT or ADT alone. The mIHC method may be a useful tool for investigating infiltrating immune cells in PCa biopsies to understand how immunotherapeutic approaches can be combined with current PCa therapies.
... The acute inflammatory response is critical for host defense and mediates antitumorigenic effects. In contrast, chronic proinflammatory stress leads to an immunosuppressive environment over time, exerting predominately anti-inflammatory features [8]. Chronic inflammation is a key feature of obesity and is also a hallmark of CC, which is linked to a phenotype characterized by a high M2/M1 macrophage ratio and secretion of immunosuppressive cytokines and chemokines by cells within the TME, such as interleukin (IL)-10 and C-C motif chemokine ligand (CCL) 22 [8]. ...
... In contrast, chronic proinflammatory stress leads to an immunosuppressive environment over time, exerting predominately anti-inflammatory features [8]. Chronic inflammation is a key feature of obesity and is also a hallmark of CC, which is linked to a phenotype characterized by a high M2/M1 macrophage ratio and secretion of immunosuppressive cytokines and chemokines by cells within the TME, such as interleukin (IL)-10 and C-C motif chemokine ligand (CCL) 22 [8]. This induces recruitment of T-helper cells and regulatory T-cells and decreased cytotoxic T-cell activity, thereby inhibiting cancer cell apoptosis [8]. ...
... Chronic inflammation is a key feature of obesity and is also a hallmark of CC, which is linked to a phenotype characterized by a high M2/M1 macrophage ratio and secretion of immunosuppressive cytokines and chemokines by cells within the TME, such as interleukin (IL)-10 and C-C motif chemokine ligand (CCL) 22 [8]. This induces recruitment of T-helper cells and regulatory T-cells and decreased cytotoxic T-cell activity, thereby inhibiting cancer cell apoptosis [8]. ...
Background:
Chronic inflammation is a key feature of obesity and a hallmark of colon cancer (CC). The obesity-related hormones leptin and adiponectin alter inflammatory gene profiles in cancer, but their specific role in CC is unclear. We have previously studied the effects of leptin and the macrophage-specific mediator itaconate on M2-like macrophages. This current study evaluates their effects on CC cells.
Methods:
HT-29 CC cells (derived from a young patient, stage III CC) were treated with either leptin, adiponectin, 4-octyl itaconate (OI) or dimethyl itaconate (DI). Gene expression after treatment was analyzed at four time points (3, 6, 18, and 24 h).
Results:
CCL22 was upregulated after treatment with adiponectin (at 18 h [FC 16.3, p < 0.001]). IL-8 expression increased following both adiponectin (at 3 h [FC 68.1, p < 0.001]) and leptin treatments (at 6 h [FC 7.3, p < 0.001]), while OI induced downregulation of IL-8 (at 24 h [FC -5.0, p < 0.001]). CXCL10 was upregulated after adiponectin treatment (at 6 h [FC 3.0, p = 0.025]) and downregulated by both OI and DI at 24 h, respectively (OI [FC -10.0, p < 0.001]; DI [FC -10.0, p < 0.001]). IL-1β was upregulated after adiponectin treatment (at 3 h [FC 10.6, p < 0.001]) and downregulated by DI (at 24 h [FC -5.0, p < 0.001]). TNF-α expression was induced following adiponectin (at 6 h [FC 110.7, p < 0.001]), leptin (at 18 h [FC 5.8, p = 0.027]) and OI (at 3 h [FC 91.1, p = 0.001]). PPARγ was affected by both OI (at 3 h [FC 10.1, p = 0.031], at 24 h [FC -10.0, p = 0.031]) and DI (at 18 h [FC -1.7, p = 0.033]).
Conclusions:
Obesity hormones directly affect inflammatory gene expression in HT29 CC cells, potentially enhancing cancer progression. Itaconate affects the prognostic marker PPARγ in HT29 CC cells. Leptin, adiponectin and itaconate may represent a link between obesity and CC.
... However, studies found that lactate resulting from stromal metabolic reprogramming could modulate CD4+T cell polarization and induces immunosuppressive behavior to promote PCa progression [74]. M2 macrophages are a class of differentiated tumor-associated macrophages (TAMs) associated with poor clinical outcomes in several cancers [75,76]. A recent study found a significant correlation between M2 macrophages and Tregs; M2 macrophages can stimulate lymphocytes to develop into Tregs to promote an immunosuppressive environment in aggressive PCa [77]. ...
The biochemical recurrence (BCR) of patients with prostate cancer (PCa) after radical prostatectomy is high, and mitochondrial respiration is reported to be associated with the metabolism in PCa development. This study aimed to establish a mitochondrial respiratory gene-based risk model to predict the BCR of PCa. RNA sequencing data of PCa were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and mitochondrial respiratory-related genes (MRGs) were sourced via GeneCards. The differentially expressed mitochondrial respiratory and BCR-related genes (DE-MR-BCRGs) were acquired through overlapping BCR-related differentially expressed genes (BCR-DEGs) and differentially expressed MRGs (DE-MRGs) between PCa samples and controls. Further, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a DE-MRGs-based risk model. Then, a nomogram was established by analyzing the independent prognostic factor of five clinical features and risk scores. Moreover, Gene Set Enrichment Analysis (GSEA), tumor microenvironment, and drug susceptibility analyses were employed between high- and low-risk groups of PCa patients with BCR. Finally, qRT-PCR was utilized to validate the expression of prognostic genes. We identified 11 DE-MR-BCRGs by overlapping 132 DE-MRGs and 13 BCR-DEGs and constructed a risk model consisting of 4 genes (APOE, DNAH8, EME2, and KIF5A). Furthermore, we established an accurate nomogram, including a risk score and a Gleason score, for the BCR prediction of PCa patients. The GSEA result suggested the risk model was related to the PPAR signaling pathway, the cholesterol catabolic process, the organic hydroxy compound biosynthetic process, the small molecule catabolic process, and the steroid catabolic process. Simultaneously, we found six immune cell types relevant to the risk model: resting memory CD4+ T cells, monocytes, resting mast cells, activated memory CD4+ T cells, regulatory T cells (Tregs), and macrophages M2. Moreover, the risk model could affect the IC50 of 12 cancer drugs, including Lapatinib, Bicalutamide, and Embelin. Finally, qRT-PCR showed that APOE, EME2, and DNAH8 were highly expressed in PCa, while KIF5A was downregulated in PCa. Collectively, a mitochondrial respiratory gene-based nomogram including four genes and one clinical feature was established for BCR prediction in patients with PCa, which could provide novel strategies for further studies.
