ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes

Lu, Zhen; McBrearty, Noreen; Chen, Jinyun; Tomar, Vivek S.; Zhang, Hongru; Rosa, Gianluca De; Tan, Aiwen; Weljie, Aalim M.; Beiting, Daniel P.; Zhang, Miao; George, Subin S.; Berger, Allison; Saggu, Gurpanna; Diehl, J. Alan; Koumenis, Constantinos; Fuchs, Serge Y.

doi:10.1016/j.cmet.2022.08.007

Cited by 37 publications

(45 citation statements)

References 53 publications

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“…Trogocytosis has been previously demonstrated for both immune cell synapses [21, 22], and in human development [23]. In CTLs, trogocytosis causes uptake of the human leukocyte antigen (HLA) MHC-I and peptide complexes from antigen-presenting cells [21, 24, 25]. Importantly, upon co-culture of human CAFs with mouse PDAC cells, we observed a similar acquisition and re-expression of human HLA proteins on the murine PDAC surface ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…From this perspective, it is perhaps not surprising that heterotypic CAF-CTL cell-cell interactions exert immunosuppressive effects upon T cells [24], similar to those elicited by membrane transfer from the malignant cells [24]. While CTLs require cholesterol for proliferation and activation [74], we and others [24, 69, 75] have demonstrated that excessive uptake of cholesterol in tumor microenvironment induces exhaustion of CD8-positive T cells. Whereas the role of PtdSer receptor TIM-3 has been previously suggested to play a role in T cell inactivation[25], our new evidence derived from pharmacological and genetic experiments ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6)

Ogier,

Solomon,

et al. 2023

Preprint

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In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6)

Ogier,

Solomon,

et al. 2023

Preprint

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“…[ 30 ] Activating ATF3 is a stress‐induced transcription factor that plays vital roles in modulating metabolism, immunity, and oncogenesis. [ 31 ] ATF3 acts as a hub of the cellular adaptive‐response network. Multiple extracellular signals, such as ER stress, cytokines, chemokines, and LPS, are connected to ATF3 induction.…”

Section: Resultsmentioning

confidence: 99%

Nano‐Econazole Enhanced PD‐L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma

Qin

Tian

et al. 2023

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Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo‐phototherapy nanoplatform is designed by which econazole and biliverdin can be co‐assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD‐L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin‐induced PTT/PDT and boost the immunotherapeutic response of PD‐L1 blockade. In addition, econazole simultaneously enhances PD‐L1 expression to sensitize anti‐PD‐L1 therapy, leading to suppression of distant tumors, long‐term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+T lymphocytes. The combined FBE NPs and α‐PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo‐phototherapy with PD‐L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

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“…Tumor-infiltrating T cells and macrophages are the key components of TIME. CD8 + T cells are cytotoxic T lymphocytes that play important roles in anti-tumor and anti-viral infections [28] . Thus, the decreased of CD5L expression and its positive correlation to CD8 + T cell infiltration level in LIHC indicated that severe immune escape occurred.…”

Section: Discussionmentioning

confidence: 99%

Exogenous CD5L inhibits liver hepatocellular carcinoma cell proliferation and role of CD5L as prognostic marker

Gao

Wu²,

Yang

et al. 2023

Chinese Medical Journal

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Background: CD5L (CD5 molecular-like) plays an important role in lipid metabolism and immune regulation. This study aimed to investigate the roles of CD5L on liver hepatocellular carcinoma (LIHC). Methods: We analyzed the CD5L mRNA expression and its potential prognostic value based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Immunohistochemical analysis was used to investigate the CD5L levels in LIHC tissues. Serum CD5L levels in LIHC were detected by enzyme-linked immunosorbent assay. Cell Counting Kit-8 (CCK-8) assay was used to investigate the effect of CD5L treatment on HepG2 and QSG-7701 cell proliferation. CD5L expression correlated genes were exhumed based on the LinkedOmics. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for CD5L associated genes were performed. The correlation between CD5L and tumor immune infiltration was analyzed by using Tumor Immune Estimation Resource (TIMER) 2.0. Results: CD5L mRNA and protein levels were significantly decreased in LIHC tumor tissue compared with non-tumor control tissues. Moreover, serum CD5L levels were significantly lower in LIHC patients than that in healthy subjects. Gene Expression Profiling Interactive Analysis 2 and Kaplan-Meier plotter analysis showed that a high-CD5L expression was correlated with favorable overall survival in LIHC patients, except the LIHC patients with hepatitis virus. CCK-8 results showed that CD5L treatment significantly decreased HepG2 cell proliferation in a concentration-dependent manner, and CD5L treatment had no effect on the proliferation of non-tumor hepatocyte line QSG-7701. CD5L associated genes were enriched in the immune response biological process, and CD5L expression levels were positively correlated with the immune infiltrates of CD8 + T cell and M1 macrophage cells but negatively correlated with CD4 + T cells and M0 macrophage cell infiltration. Conclusions: Exogenous CD5L inhibits cell proliferation of hepatocellular carcinoma. CD5L may act as a role of prognostic marker.

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ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes

Cited by 37 publications

References 53 publications

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6)

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6)

Nano‐Econazole Enhanced PD‐L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma

Exogenous CD5L inhibits liver hepatocellular carcinoma cell proliferation and role of CD5L as prognostic marker

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