IFNγ-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2–Mediated Inhibition of Antitumor CTL Responses

Basingab, Fatemah; Ahmadi, Maryam; Morgan, David

doi:10.1158/2326-6066.cir-15-0146

Cited by 48 publications

(39 citation statements)

References 46 publications

(59 reference statements)

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“…While both these 2 molecules have the capability to suppress T cell responses, this is not due to a direct on T cells but is rather mediated by other cell types like dendritic cells, myeloid-derived suppressor cells, M2 macrophages and Treg cells. [38][39] Additionally, it is also possible that immunosuppressive elements like prostaglandins, 40 kynurenins 41 or potassium 42 may be responsible. Therefore, additional studies are needed to find out the molecule responsible for the immunosuppressive activities of the colon CSC secretome on ab and gd T cells.…”

Section: Discussionmentioning

confidence: 99%

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer

et al. 2017

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γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% γδ T cells on average, with the majority expressing Vδ1. Most Vδ1 and Vδ2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- γ which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant γδ T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.

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Section: Discussionmentioning

confidence: 99%

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer

et al. 2017

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“…PGE 2 also suppresses the cytotoxic activity of CD8 + T cells by upregulation of CD94 and the NKG2A C-type lectin receptor complex (161) or by attenuating T cell receptor-induced IFN-γ release (162). Moreover, PGE 2 produced by metastatic renal carcinoma cells shifted CD8 + CTLs toward tumor antigen-specific tolerance during interaction of CTLs and tumor cells (163). Clearly, these in vitro results need to be confirmed in animal models of gastrointestinal cancer.…”

Section: Pge 2 and T Cellsmentioning

confidence: 98%

Role of prostanoids in gastrointestinal cancer

Wang¹,

DuBois²

2018

Journal of Clinical Investigation

126

124

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Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.

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“…39 In addition, the production of prostaglandin E2 in the tumor microenvironment downregulates the expression of ICAM-1 in tumor cells, reducing the cytotoxic effects of T cells. 40 Thus, ICAM-1 could be a potential target for cancer immunotherapy. However, in some reports, the expression of ICAM-1 has been shown to be positively correlated with a more aggressive tumor phenotype and metastatic potential, 38,41 suggesting that ICAM-1 is not a good primary target protein for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an ‘inside-out’ activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2–actin–LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.

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IFNγ-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2–Mediated Inhibition of Antitumor CTL Responses

Cited by 48 publications

References 46 publications

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer

Role of prostanoids in gastrointestinal cancer

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

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