scholarly journals The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 189
Author(s):  
Linda Bilonda Mutala ◽  
Cécile Deleine ◽  
Matilde Karakachoff ◽  
Delphine Dansette ◽  
Kathleen Ducoin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Explant Culture ◽  
T Cell Response ◽  
Mrna Levels ◽  
Innate And Adaptive Immunity ◽  
Caspase 1 ◽  
Culture Model

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23087-e23087
Author(s):  
Anne Jarry ◽  
Adrien Ouairy ◽  
Delphine Dansette ◽  
Cécile Deleine ◽  
Nicolas Jouand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Retrospective Cohort ◽  
Ex Vivo ◽  
High Density ◽  
Antitumor Immune Response ◽  
Caspase 1 ◽  
Active Caspase

e23087 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNγ) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with i) the microsatellite stable (MSS) or unstable (MSI) status of CRC, and ii) the levels of cytokines (IL18, IFNγ) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNγ response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNγ release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Rα), cultured with rhIL18, were able to secrete IFNγ either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.

Role of the inflammasome of tumor cells in modulating the biology of Tumor Infiltrating T lymphocytes (TILs) in colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 640-640
Author(s):  
Celine Bossard ◽  
Delphine Dansette ◽  
Adrien Ouairy ◽  
Nicolas Jouand ◽  
Romain Oger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Retrospective Cohort ◽  
Ex Vivo ◽  
High Density ◽  
Antitumor Immune Response ◽  
Caspase 1 ◽  
Active Caspase

640 Background: In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the phenotype and biology of Tumor Infiltrating T lymphocytes (TILs) of the tumor microenvironment. One of these mechanisms could be the inflammasome, a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL18 and generate a mucosal Th1/Tc1 (IFNg) response. However, the inflammasome status of tumor cells in CRC and its potential role on TILs are unknown yet. Methods: Prospective and retrospective cohort studies aimed to determine in CRC patients: the status of the inflammasome in tumor cells (IL18 immunostaining on tissue microarrays (TMA) and in situ detection of active caspase-1 on frozen sections) and the density of TILs (CD8+, T-bet+) in relation with the microsatellite stable (MSS) or unstable (MSI) status of CRC, and the levels of cytokines (IL18, IFNg) secreted in an ex vivo explant culture model of CRC. Finally, we assessed the effect of recombinant human IL18 (rhIL18) on the IFNg response of isolated TILs. Results: TMA analysis of the retrospective cohort showed that IL18 was significantly expressed (in more than 50% of tumor cells) in 80% of CRC, especially in MSI CRC, and correlated with a high density of T-bet+ and CD8+ intraepithelial TILs (IEL-TILs). Active caspase-1 was detected in tumor cells in 60% of CRC. In the prospective cohort, the presence of active caspase-1 in tumor cells was associated with high levels of mature IL18 secreted in explant cultures, with high density of T-bet+ TILs and with IFNg release in most cases. In addition, isolated TILs expressing IL18 receptors (IL18Ra), cultured with rhIL18, were able to secrete IFNg either unstimulated or stimulated with OKT3. Conclusions: The inflammasome of tumor cells, when maintained and active, can contribute to a Th1/Tc1 antitumor immune response elicited by TILs, that can modulate tumor growth. The inflammasome of tumor cells can thus be considered as a potential new therapeutic target to strengthen the antitumor immune response in CRC, in association with other immunotherapies.

Improvement of immune response after radiofrequency ablation in colorectal cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 102-102 ◽  
Author(s):  
Katia Lemdani ◽  
Nathalie Mignet ◽  
Johanne Seguin ◽  
Frederique Peschaud ◽  
Jean-François Emile ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Radiofrequency Ablation ◽  
T Lymphocytes ◽  
Immune Escape ◽  
Liver Tumors ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
T Cell Response

102 Background: Radiofrequency ablation (RFA) efficiency of liver tumors is compromised by high rates of relapse. Death of cancer cells by hyperthermia induced tumor antigen releasing, expression of danger signals that activate a specific T-cell response. This effect is ineffective to avoid recurrence. We propose to combine RFA with priming of a strong immune antitumor response as curative treatment of an aggressive colorectal cancer (CRC) in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor as primary lesion. In two distinct clinical situations, macroscopic or microscopic distant tumors were established as secondary lesions. The immune response was modulated by the injection, in the treated area, of a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting recruitment and maturation of dendritic cells. In mice with far large lesions, this strategy was combined with PD1checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of tumoral lymphocyte infiltration TNF-α and IFN-y expression in peripheral T lymphocytes. Results: The in situ immunogel injection after RFA resulted in prolonged survival of mice. Regression of distant lesions was related to the induction of a strong systemic antitumor immune response and a great improvement of tumor infiltration by CD3+ T lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without another treatment. Immune escape of large secondary lesions was reversed by association of the RFA-immunogel vaccination with a systemic immune checkpoint inhibition, separately ineffective. Conclusions: Validation of this strategy, combining RFA of macroscopic lesions and activation of a strong immune response controlling the residual disease, could result in the design of a clinical assay including this approach within a standard treatment of colorectal liver metastases. The synergy between in situ immunomodulation as priming process and checkpoint blockade, ineffective alone in metastatic microsatellite stable CRC or after single RFA, allows reconsidering the use of checkpoint inhibitors in CRC.

STING-mediated Syk Signaling Attenuates Tumorigenesis of Colitis‑associated Colorectal Cancer Through Enhancing Intestinal Epithelium Pyroptosis

2021 ◽  
Author(s):  
Wenbin Gong ◽  
Peizhao Liu ◽  
Fan Zhao ◽  
Juanhan Liu ◽  
Zhiwu Hong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Human Colon ◽  
Physical Interaction ◽  
Human Colon Cancer ◽  
Human Colon Cancer Cells ◽  
Cells Death ◽  
Induce Cancer Cell Apoptosis

Abstract Background Stimulator of interferon genes (STING) has essential functions in the immune responses and can induce cancer cell apoptosis. However, it is not completely clear how STING plays a role in colitis-associated colorectal cancer (CAC) and whether it can trigger pyroptosis during the tumorigenesis of CAC. Methods To investigate the role of STING-modulated pyroptosis in the development of CAC, STING knockout and Wild type mice were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to establish a murine CAC model. STING pharmacological agonist was used to further study the functions of STING signaling in the tumorigenesis. Moreover, STING endogenous ligand was employed to verify the effects of STING in human colon cancer cells. Results STING deficiency mice were more susceptible to CAC by reducing pyroptosis of tumor cells, whereas overactivation of STING with the agonist suppressed tumorigenesis of CAC. STING also managed CAC development by modulating tumor cells proliferation, adhesion, and invasion, as well as inflammatory response. The ex vivo studies indicated that STING could induce pyroptosis via spleen tyrosine kinase (Syk), and Syk knockdown weakened such pyroptotic tumor cells death. In addition, the visible physical interaction between STING and Syk was observed in colorectal tumor samples of CAC patients. Conclusions STING-mediated Syk signaling may regulate the tumorigenesis of CAC by modulating pyroptosis of tumor cells, and modulation of STING/Syk serves as a novel therapeutic strategy for CAC therapy.

scholarly journals P11.10 The IFNγ pathway mediates brain metastasis formation of breast cancer

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii44-iii44
Author(s):  
R Pedrosa ◽  
J M Kros ◽  
B Schrijver ◽  
R Marques ◽  
P Leenen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells

Abstract BACKGROUND In previous work we showed the prominence of the T-cell response in the formation of brain metastases of primary ER negative breast cancers (Mustafa et al, Acta Neuropathol 2018). We also showed that breast cancer cells co-cultured with stimulated T lymphocytes overexpress Guanylate-binding protein 1 (GBP1) accompanying increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. We now scrutinize the importance of the IFNγ pathway for tresspassing of the tumor cells through the BBB following T cell contact. MATERIAL AND METHODS Anti-hIFN-γ-IgA antibodies were used to neutralize the IFNγ effects on the tumor cells. The effects on the tumor cells is only due to native IFNγ produced by activated T cells, not by recombinant IFNγ. Since the IFNγ expression itself enhances its expression by the T cells, we blocked IFNγ receptors prior to adding CD3+ T cell conditioned media to the breast cancer cells. The receptor blocking was achieved by antibodies to the IFNγα and IFNγβ subunits. Activation of the STAT1 pathway was monitored by GBP1 expression. For functional read-out the in vitro BBB model was used. RESULTS The presence of T-lymphocyte-secreted IFNγ in the primary breast cancer microenvironment activates the STAT1-dependent IFNγ pathway in breast cancer cells, endowing them with an increased ability to trespass the in vitro BBB. Moreover, direct inhibition of soluble IFNγ, or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. CONCLUSION The results illustrate the specific action of T lymphocytes in the formation of cerebral metastasis involves the IFNγ signaling pathway as one of the crucial entangled pathways Subsequent studies should aim at the interference with the IFNγ pathway to develop preventive strategies against the formation of cerebral metastases of breast cancer.

scholarly journals Modulation of CD4 T Cell Response According to Tumor Cytokine Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 373
Author(s):  
Théo Accogli ◽  
Mélanie Bruchard ◽  
Frédérique Végran
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Tumor Biology ◽  
T Cell Response ◽  
Close Link ◽  
Innate And Adaptive Immunity ◽  
Tumor Bed ◽  
The Past ◽  
The Impact

The advancement of knowledge on tumor biology over the past decades has demonstrated a close link between tumor cells and cells of the immune system. In this context, cytokines have a major role because they act as intermediaries in the communication into the tumor bed. Cytokines play an important role in the homeostasis of innate and adaptive immunity. In particular, they participate in the differentiation of CD4 T lymphocytes. These cells play essential functions in the anti-tumor immune response but can also be corrupted by tumors. The differentiation of naïve CD4 T cells depends on the cytokine environment in which they are activated. Additionally, at the tumor site, their activity can also be modulated according to the cytokines of the tumor microenvironment. Thus, polarized CD4 T lymphocytes can see their phenotype evolve, demonstrating functional plasticity. Knowledge of the impact of these cytokines on the functions of CD4 T cells is currently a source of innovation, for therapeutic purposes. In this review, we discuss the impact of the major cytokines present in tumors on CD4 T cells. In addition, we summarize the main therapeutic strategies that can modulate the CD4 response through their impact on cytokine production.

scholarly journals The cellular genomic diversity, regulatory states and networking of the metastatic colorectal cancer microenvironment

2020 ◽  
Author(s):  
Anuja Sathe ◽  
Susan M. Grimes ◽  
Billy T. Lau ◽  
Xiangqi Bai ◽  
Jiamin Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Normal Tissue ◽  
Ex Vivo ◽  
Metastatic Tumor ◽  
Cell Types ◽  
Genomic Diversity ◽  
Clonal Variation ◽  
Lineage Differentiation

ABSTRACTMetastatic colorectal cancer (mCRC) involves tumor cells seeding distant organs. Metastatic CRC genome biology has intrinsic properties related to heterogeneous clonal tumor cells and extrinsic properties of the cellular niche of the tumor microenvironment (TME). To characterize mCRC’s cell types and states, we used single-cell RNA sequencing (scRNA-seq) and DNA sequencing (scDNA-seq) on metastases in the liver and omentum, a tissue lining the abdomen. We performed scRNA-seq on 49,637 cells derived from mCRC, paired normal tissue and peripheral blood. We performed whole genome scDNA-seq on 3,683 mCRC cells from the same samples. These metastases had intrinsic heterogeneity, with clone-specific copy number variation and lineage differentiation. For the extrinsic niche, TME macrophages had a cellular state resembling cirrhotic macrophages and foam cells with indicators of increased activity for extracellular matrix (ECM) organization. TME fibroblasts had an expression program influencing ECM composition that was not observed in matched normal tissue. Only a few CD8 T cells were present among the liver mCRCs, indicating immune exclusion. Receptor-ligand analysis revealed that TME macrophages and fibroblasts formed an interactome, thus providing intercellular coordination which increased T cell exhaustion and exclusion. For one mCRC, we used in a patient-derived ex vivo tissue model that captures the TME components of the original metastatic tumor, applied specific perturbations to the TME immune cells and evaluated cellular state changes with scRNA-seq. Overall, our study identified tumor cell clonal variation, characterized specific TME properties of the CRC metastatic niche and demonstrated an experimental model of perturbing the cellular TME milieu.

scholarly journals MicroRNA-224 Suppresses Colorectal Cancer Cell Migration by Targeting Cdc42

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Tao-Wei Ke ◽  
Han-Lin Hsu ◽  
Yu-Hua Wu ◽  
William Tzu-Liang Chen ◽  
Ya-Wen Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Tumor Cells ◽  
Ectopic Expression ◽  
Predictive Biomarker ◽  
Expression Level ◽  
Mrna Levels ◽  
Clinical Prognosis ◽  
Rna Targets ◽  
Multistep Process

The metastatic spread of tumor cells is the major risk factor affecting the clinical prognosis of colorectal cancer (CRC) patients. The metastatic phenotype can be modulated by dysregulating the synthesis of different structural and functional proteins of tumor cells. Micro(mi)RNAs are noncoding RNAs that recognize their cognate messenger (m)RNA targets by sequence-specific interactions with the 3′ untranslated region and are involved in the multistep process of CRC development. The objective of this study was to investigate the expression and biological roles of miR-224 in CRC. The miR-224 expression level was assessed by a quantitative real-time PCR in 79 CRC and 18 nontumor tissues. Expression levels of miR-224 in CRC tissues were significantly lower than those in nontumor tissues. Its expression level was associated with the mutation status of the APC gene. Ectopic expression of miR-224 suppressed the migratory ability of CRC cell line, but cell proliferation was less affected. Increased miR-224 diminished Cdc42 and SMAD4 expressions at both the protein and mRNA levels and inhibited the formation of actin filaments. Overall, this study indicated a role of miR-224 in negatively regulating CRC cell migration. The expression level of miR-224 may be a useful predictive biomarker for CRC progression.

scholarly journals Abstract 4061: The inflammasome of tumor cells modulates the biology of tumor-infiltrating T lymphocytes in colorectal cancer

2018 ◽  
Author(s):  
Linda Bilonda ◽  
Delphine Dansette ◽  
Cecile Deleine ◽  
Romain Oger ◽  
Nicolas Jouand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Lymphocytes ◽  
Tumor Cells
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