FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression

Chen, Lingling; Qiu, Xiangting; Wang, Xinhua; He, Jie

doi:10.1016/j.bbrc.2017.03.039

Cited by 84 publications

(81 citation statements)

References 19 publications

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“…In the tissue with chronic colitis, CCL-2 but not FAPα was also significantly high compared to the control (Figure 2). These findings are consistent with other reports in cancerous tissues (Henriksson et al, 2011;Chen et al, 2017).…”

Section: Expressions Of Oxt Oxtr Fapα and Ccl-2 In The Cac Chipssupporting

confidence: 94%

“…It was also reported that peripheral use of OXT reduced stress-induced visceral hypersensitivity and activation of enteric glial reactivity (Xu et al, 2018), thereby increasing the defense of GI tract to inflammatory challenges. In the present study, we also found that OXT can reduce the expression of CCL-2, which helps to restore immune checkpoint blockade and increase T-cell activity to inhibit the development of CRCs (Chen et al, 2017). Nevertheless, there is still a need to collect direct evidence of the suppression effect of OXT from CRC in vivo; OXT can suppress carcinogenesis at multiple levels including the colon tissue as discussed below.…”

Section: General Anticancer Effect Of Oxt and Its Approachessupporting

confidence: 63%

“…the expression of FAPα. Clearly, both CCL-2 and TGF-β are the downstream signals of FAPα (Henriksson et al, 2011;Meulendijks et al, 2016;Chen et al, 2017;Mohr et al, 2017), and OXT decreased CCL-2 expression but not TGF-β. Thus, the major downstream signal of OXTR-FAPα signaling is CCL-2 but not TGF-β.…”

Section: Inhibitory Effects Of Oxt On Crc Migrationmentioning

confidence: 94%

“…CRC cells, but not adenoma cells, can activate fibroblasts by inducing FAPα expression in order to increase their migration and invasion by releasing the transforming growth factor (TGF; Hawinkels et al, 2014). Furthermore, in mouse CRC model, cancer-associated fibroblasts with high FAPα expression induce resistance to immune checkpoint blockade by upregulating C-C motif chemokine ligand 2 (CCL-2) secretion, recruiting myeloid cells, and decreasing T-cell activity (Chen et al, 2017). Therefore, clarifying the regulation of FAPα expression in cancer-associated fibroblasts and its associated cytokines probably provide an optional target for suppressing CRC migration.…”

Section: Introductionmentioning

confidence: 99%

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Oxytocin Inhibition of Metastatic Colorectal Cancer by Suppressing the Expression of Fibroblast Activation Protein-α

Chen

et al. 2019

Front. Neurosci.

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Oxytocin (OXT) and its receptor (OXTR) are present in the gastrointestinal system and are involved in gastrointestinal tumorigenesis. However, the effect of OXTR signaling on the development of colorectal cancer (CRC) and its underlying mechanisms remain unexplored. To address these issues, we first examined the expressions of OXT, OXTR, and several cancer-associated proteins using colon "tissue chips" from a spectrum of malignant progression of the colon, which included normal colon tissue, chronic colitis, colorectal adenoma, and colorectal adenocarcinoma (CAC). The results showed that the expressions of OXT and OXTR decreased gradually with the malignant progression of the disease. Stimulation of CAC tissues with OXT increased OXTR expression while down-regulated FAPα and CCL-2 protein expressions in a concentration-and timedependent manner. Moreover, cell invasion experiment showed that OXT treatment reduced the invasion ability of colon cancer cells and blocking OXTR with atosiban blocked OXT-reduced invasion ability of human colon cancer cell lines Ls174T and SW480. The results indicate that OXT has the potential to inhibit CRC development via down-regulating the immunosuppressive proteins FAPα and CCL-2. When the OXTR signaling is weakened, colon tissues may transform to CRC. These findings also highlight the possibility of applying OXT to inhibit CRC development directly.

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Section: Expressions Of Oxt Oxtr Fapα and Ccl-2 In The Cac Chipssupporting

confidence: 94%

Section: General Anticancer Effect Of Oxt and Its Approachessupporting

confidence: 63%

Section: Inhibitory Effects Of Oxt On Crc Migrationmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Oxytocin Inhibition of Metastatic Colorectal Cancer by Suppressing the Expression of Fibroblast Activation Protein-α

Chen

et al. 2019

Front. Neurosci.

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“…Incipient data are showing the role of the AXL in the paracrine feedback loop between cancer and fibroblastic cells with significant effects on resistance to conventional therapies, and likely, immunotherapy [149], paving the way for the design of new therapeutic strategies combining AXL targeting with ICBs. Growing evidence shows that FAP, selectively expressed on CAF subtypes and associated with ECM remodeling, induces tumor-promoting inflammation [150][151][152]. Furthermore, as mentioned before, FAP targeting has been shown to synergize with ICB-based immunotherapy [120,150,152].…”

Section: Tumor-extrinsic Factors Fostering Icb Resistancementioning

confidence: 99%

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

Trono¹,

Sistigu

Palermo³

et al. 2017

Emerging Topics in Life Sciences

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Correspondence: Paola Nisticò ( paola.nistico@ifo.gov.it)Targeting of immune checkpoint blockers (ICBs), such as cytotoxic T-lymphocyte antigen-4 and programmed-death 1/programmed-death ligand 1, has dramatically changed the landscape of cancer treatment. Seeing patients who were refractory to conventional therapy recover after immunotherapy, with high rates of objective durable responses and increased overall survival, has raised great enthusiasm in cancer care and research. However, to date, only a restricted portion of patients benefit from these therapies, due to natural and acquired resistance relying on the ever-evolving cross-talk between tumor and stromal cells. Here, we review the convergence of tumor-intrinsic and -extrinsic cues, both affecting tumor plasticity and tumor stroma leading to an immunosuppressive tumor microenvironment, which may account for the heterogeneous responses and resistance to ICB therapies. A deeper knowledge of the mechanisms and fingerprints involved in natural and acquired resistance is likely to bring clinical benefit to the majority of patients, offering important clues for overcoming drug resistance and boosting the effectiveness of treatment. We discuss the need to define tumor subtypes based on the tumor, immune and stromal gene signature and propose that the better we understand tumor mesenchymal traits, the more we will be able to identify predictive biomarkers of response to ICB treatments.

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Cytokine‐ and chemokine‐induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy

Bhat

Nisar

Singh

et al. 2022

Cancer Communications

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Colorectal cancer (CRC) is a predominant life‐threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer‐associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix‐remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell‐like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine‐ and chemokine‐mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine‐ and chemokine‐mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.

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FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression

Cited by 84 publications

References 19 publications

Oxytocin Inhibition of Metastatic Colorectal Cancer by Suppressing the Expression of Fibroblast Activation Protein-α

Oxytocin Inhibition of Metastatic Colorectal Cancer by Suppressing the Expression of Fibroblast Activation Protein-α

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

Cytokine‐ and chemokine‐induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy

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