From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts

Arpinati, Ludovica; Scherz-Shouval, Ruth

doi:10.1016/j.trecan.2023.01.007

Cited by 30 publications

(21 citation statements)

References 153 publications

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“…Next, we took a closer look at the ligand expression levels of CAF subpopulations, to infer their roles in regulating anti‐tumour immune responses (Figure 2E). C01_CCL11 and C06_CCL2 were similar in ligand expression patterns, and they might attract eosinophils, basophils, or CCR5 + T cells through producing high levels of CCL2, CCL3, CCL11 and CCL21 52 . The ligands enriched in C02_POSTN and C07_MKI67 included the Transforming Growth Factor‐β (TGF‐β) superfamily and WNT/β‐catenin pathway genes, such as TGFB1, TGFB2, TGFB3, INHBA and WNT5A suggesting that they might be closely related to the exclusion of T cells and immune evasion 53,54 .…”

Section: Resultsmentioning

confidence: 96%

Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Chen,

Guo,

Liu

et al. 2023

Clinical & Translational Med

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BackgroundCancer‐associated fibroblasts (CAFs) are potential targets for cancer therapy. Due to the heterogeneity of CAFs, the influence of CAF subpopulations on the progression of lung cancer is still unclear, which impedes the translational advances in targeting CAFs.MethodsWe performed single‐cell RNA sequencing (scRNA‐seq) on tumour, paired tumour‐adjacent, and normal samples from 16 non‐small cell lung cancer (NSCLC) patients. CAF subpopulations were analyzed after integration with published NSCLC scRNA‐seq data. SpaTial enhanced resolution omics‐sequencing (Stereo‐seq) was applied in tumour and tumour‐adjacent samples from seven NSCLC patients to map the architecture of major cell populations in tumour microenvironment (TME). Immunohistochemistry (IHC) and multiplexed IHC (mIHC) were used to validate marker gene expression and the association of CAFs with immune infiltration in TME.ResultsA subcluster of myofibroblastic CAFs, POSTN+ CAFs, were significantly enriched in advanced tumours and presented gene expression signatures related to extracellular matrix remodeling, tumour invasion pathways and immune suppression. Stereo‐seq and mIHC demonstrated that POSTN+ CAFs were in close localization with SPP1+ macrophages and were associated with the exhausted phenotype and lower infiltration of T cells. POSTN expression or the abundance of POSTN+ CAFs were associated with poor prognosis of NSCLC.ConclusionsOur study identified a myofibroblastic CAF subpopulation, POSTN+ CAFs, which might associate with SPP1+ macrophages to promote the formation of desmoplastic architecture and participate in immune suppression. Furthermore, we showed that POSTN+ CAFs associated with cancer progression and poor clinical outcomes and may provide new insights on the treatment of NSCLC.

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Section: Resultsmentioning

confidence: 96%

Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Chen,

Guo,

Liu

et al. 2023

Clinical & Translational Med

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“…In our study, using trajectory analysis, we found that CAFs transitioned from normal to iCAFs and then to myCAFs in two datasets of breast and pancreatic tumors, with a corresponding decrease in OSR along this trajectory. Understanding the mechanisms behind the effect of oxidative stress on fibroblasts transformations could provide valuable insights into how 20 to leverage this process for therapeutic benefits, particularly since iCAFs have been shown to attract immune cells and enable a more anti-tumorigenic environment, compared to myCAFs (Arpinati & Scherz-Shouval, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…CAFs, a heterogeneous population originating from various sources, are generally divided into three - myofibroblastic CAFs (myCAFs), immune-regulatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs)(Sahai et al , 2020; Ping et al , 2021; Santi et al , 2018; Ganguly et al , 2020; Liu et al , 2019; Chen et al , 2021b). They interact with other cells of the TME, such as immune cells, facilitating a pro-tumorigenic environment (Liu et al , 2019; Lavie et al , 2022; Elyada et al , 2019; Arpinati & Scherz-Shouval, 2023; Mun et al , 2022). Pericytes, mural cells of blood vessels, are involved in tumor angiogenesis and metastasis, regulating vascular stability, and enhancing tumor cell intravasation when dysfunctional (Armulik et al , 2011; Sun et al , 2021).…”

Section: Introductionmentioning

confidence: 99%

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

Lior,

Barki,

Iacobuzio-Donahue

et al. 2023

Preprint

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The tumor microenvironment (TME) is a challenging environment where cells must cope with stressful conditions such as fluctuating pH levels, hypoxia, and free radicals. In response, stress pathways are activated, which can both promote and inhibit tumorigenesis. In this study, we set out to characterize the stress response landscape across four carcinomas: breast, pancreas, ovary, and prostate tumors, focusing on five pathways: Heat shock response, oxidative stress response, unfolded protein response, hypoxia stress response, and DNA damage response. Using a combination of experimental and computational methods, we create an atlas of the stress response landscape across various types of carcinomas. We find that stress responses are heterogeneously activated in the TME, and highly activated near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering new ways to intersect survival pathways within the tumor, and advance cancer therapy.

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“…Cancer-associated fibroblasts constitute a key component within tumor stroma, which exert multifaceted roles in the TME. 149 The phenotype and function of neutrophils are affected by CAFs. For instance, CAFs prime PDL1+ neutrophils via IL-6-STAT3 signaling, which foster immune suppression in HCC.…”

Section: Cancer-associated Fibroblasts (Cafs)mentioning

confidence: 99%

“…Cancer‐associated fibroblasts constitute a key component within tumor stroma, which exert multifaceted roles in the TME 149 . The phenotype and function of neutrophils are affected by CAFs.…”

Section: Crosstalk Between Netosis and The Tme: From Cancer Initiatio...mentioning

confidence: 99%

NETosis: Sculpting tumor metastasis and immunotherapy

Hu,

Wang,

Liu

2023

Immunological Reviews

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SummaryThe process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, recent work has revealed the unique biology of NETosis in facilitating tumor metastatic process. Neutrophil extracellular traps released by the tumor microenvironment (TME) shield tumor cells from cytotoxic immunity, leading to impaired tumor clearance. Besides, tumor cells tapped by NETs enable to travel through vessels and subsequently seed distant organs. Targeted ablation of NETosis has been proven to be beneficial in potentiating the efficacy of cancer immunotherapy in the metastatic settings. This review outlines the impact of NETosis at almost all stages of tumor metastasis. Furthermore, understanding the multifaceted interplay between NETosis and the TME components is crucial for supporting the rational development of highly effective combination immunotherapeutic strategies with anti‐NETosis for patients with metastatic disease.

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From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts

Cited by 30 publications

References 153 publications

Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

NETosis: Sculpting tumor metastasis and immunotherapy

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From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts

Cited by 30 publications

References 153 publications

Single‐cell and spatial transcriptomics reveal POSTN+ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Single‐cell and spatial transcriptomics reveal POSTN+ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

NETosis: Sculpting tumor metastasis and immunotherapy

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Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer

Single‐cell and spatial transcriptomics reveal POSTN⁺ cancer‐associated fibroblasts correlated with immune suppression and tumour progression in non‐small cell lung cancer