Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

Koppensteiner, Lilian; Mathieson, Layla; O’Connor, Richard A.; Akram, Ahsan

doi:10.3389/fimmu.2022.887380

Cited by 31 publications

(18 citation statements)

References 93 publications

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“…There is increasing interest in the role of stromal cells in tumour immunity. 36–39 Our data illustrates CD39 and CD73 expression on stromal cells with characteristic shape of fibroblasts and which are in close proximity to T cells. We have previously described bidirectional upregulation of CD39 and CD73 elicited by CAF – T cell crosstalk.…”

Section: Discussionmentioning

confidence: 66%

Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Koppensteiner

Mathieson

Pattle

et al. 2022

Preprint

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An improved mechanistic understanding of immunosuppressive pathways in NSCLC is important to develop novel diagnostic and therapeutic approaches. Here, we reveal that the prognostic significance of the rate limiting ectonucleotidases in adenosine production CD39 and CD73 requires knowledge of cell type specific expression and localisation within tumours. In a cohort of early treatment naive NSCLC patients, high stromal expression of CD39 and CD73 predicts poor outcome. CD39 expression amongst T cells identifies CD39+CD4+ Tregs which predict poor outcome and CD39+CD103+ CTL which confer a survival benefit if high densities are observed inside of the tumour nest. Bulk RNA Seq shows that the TME of NSCLC upregulates regulatory pathways in CD4+ T cells and exhaustion in CD8+ T cells. Analysis of single-cell RNASeq datasets illustrates that CD39+CD4+ Tregs are enriched in Treg signature gene sets, and CD39+CD103+ CTL show gene signatures indicative of an exhausted cytotoxic phenotype with an upregulated expression of CXCL13. Combined knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39+ T cell populations in NSCLC. This study provides an improved understanding of the spatial and functional characteristics of CD39+ T cells and illustrates their significance to patient outcome.

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Section: Discussionmentioning

confidence: 66%

Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Koppensteiner

Mathieson

Pattle

et al. 2022

Preprint

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“…Though the CAF secretome is still not fully characterized, there is evidence that CAF-secreted cytokines and growth factors may trigger the immunosuppressive functions that involve various immune cells and stages of anti-tumoral activity [ 50 , 51 ]. Recent studies have highlighted the direct implication of CAFs in the tumor immunosuppressive microenvironment by excluding T-cells from tumors [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells

et al. 2022

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Background Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, contribute to an immunosuppressive tumor microenvironment (TME) through the induction and functional polarization of protumoral macrophages. We have herein investigated the contribution of CAFs to monocyte recruitment and macrophage polarization. We also sought to identify a possible paracrine mechanism by which CAF-educated monocytes affect breast cancer (BC) cell progression. Methods Monocytes were educated by primary CAFs and normal fibroblast (NF); the phenotypic alterations of CAF- or NF-educated monocytes were measured by flow cytometry. Exosomes isolated from the cultured conditioned media of the educated monocytes were characterized. An in vivo experiment using a subcutaneous transplantation tumor model in athymic nude mice was conducted to uncover the effect of exosomes derived from CAF- or NF-educated monocytes on breast tumor growth. Gain- and loss-of-function experiments were performed to explore the role of miR-181a in BC progression with the involvement of the AKT signaling pathway. Western blotting, enzyme-linked immunosorbent assay, RT-qPCR, flow cytometry staining, migration assay, immunohistochemical staining, and bioinformatics analysis were performed to reveal the underlying mechanisms. Results We illustrated that primary CAFs recruited monocytes and established pro-tumoral M2 macrophages. CAF may also differentiate human monocyte THP-1 cells into anti-inflammatory M2 macrophages. Besides, we revealed that CAFs increased reactive oxygen species (ROS) generation in THP-1 monocytes, as differentiating into M2 macrophages requires a level of ROS for proper polarization. Importantly, T-cell proliferation was suppressed by CAF-educated monocytes and their exosomes, resulting in an immunosuppressive TME. Interestingly, CAF-activated, polarized monocytes lost their tumoricidal abilities, and their derived exosomes promoted BC cell proliferation and migration. In turn, CAF-educated monocyte exosomes exhibited a significant promoting effect on BC tumorigenicity in vivo. Of clinical significance, we observed that up-regulation of circulating miR-181a in BC was positively correlated with tumor aggressiveness and found a high level of this miRNA in CAF-educated monocytes and their exosomes. We further clarified that the pro-oncogenic effect of CAF-educated monocytes may depend in part on the exosomal transfer of miR-181a through modulating the PTEN/Akt signaling axis in BC cells. Conclusions Our findings established a connection between tumor stromal communication and tumor progression and demonstrated an inductive function for CAF-educated monocytes in BC cell progression. We also proposed a supporting model in which exosomal transfer of miR-181a from CAF-educated monocytes activates AKT signaling by regulating PTEN in BC cells.

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“…Previous studies have shown that lymphocytes have a key role in anti-cancer immunity ( 31 ). Circulating monocytes in the cancer microenvironment differentiate into macrophages ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Predictive value of modified systemic inflammation score for postoperative unplanned ICU admission in patients with NSCLC

Wang

Zhang²,

Huang³

et al. 2022

Front. Surg.

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BackgroundThe purpose of this study was to investigate the predictive value of the modified systemic inflammation score (mSIS) in postoperative unplanned admission to the intensive care unit (ICU) in patients with non-small-cell lung cancer (NSCLC).MethodsThe clinical data of 1,321 patients with NSCLC treated with thoracic surgery in our hospital from August 2019 to June 2021 were analyzed retrospectively. The preoperative mSIS, which takes into account the serum albumin (ALB) level and lymphocyte-to-monocyte ratio (LMR), was recorded as 0, 1 or 2 and then was used to identify high-risk patients with unplanned admission to the ICU. The independent risk factors for unplanned admission to the ICU in patients with NSCLC after surgery were identified by multivariate logistic regression analysis.ResultsA total of 1,321 patients, including 549 (41.6%) males and 772 (58.4%) females, were included. The median age was 57 years (range 16–95 years). The incidence of unplanned admission to the ICU in patients with mSIS = 2 was significantly higher than that in those with mSIS = 0 and mSIS = 1. The multivariate analysis showed that an mSIS of 2 (OR = 3.728; P = 0.004; 95% CI, 1.520–9.143), an alcohol consumption history (OR = 2.791, P = 0.011; 95% CI, 1.262–6.171), intraoperative infusion volume (OR = 1.001, P = 0.021; 95% CI, 1.000–1.001) and preoperative underlying diseases (OR = 3. 57, P = 0.004; 95% CI, 1.497–8.552) were independent risk factors for unplanned admission to the ICU after lung cancer surgery. In addition, the multivariate logistic regression model showed that the C-statistic value was 0.799 (95% CI: 0.726∼0.872, P < 0.001).ConclusionsThe mSIS scoring system can be used as a simplified and effective predictive tool for unplanned ICU admission in patients with NSCLC.

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Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

Cited by 31 publications

References 93 publications

Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells

Predictive value of modified systemic inflammation score for postoperative unplanned ICU admission in patients with NSCLC

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