Dendritic Cells Recruit T Cell Exosomes via Exosomal LFA-1 Leading to Inhibition of CD8+ CTL Responses through Downregulation of Peptide/MHC Class I and Fas Ligand-Mediated Cytotoxicity

Xie, Yufeng; Zhang, Haifeng; Li, Wei; Deng, Yulin; Munegowda, Manjunatha Ankathatti; Chibbar, Rajni; Qureshi, Mabood; Xiang, Jim

doi:10.4049/jimmunol.1000386

Cited by 105 publications

(89 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 However, under certain conditions, Fas signaling can exert non-apoptotic effects, including inflammatory responses, liver regeneration, increased branching of developing neurons, migration of cells, angiogenesis, fibrosis, proliferation and differentiation of cells and advancement of the cell cycle. [6][7][8][9][10][11] Therefore, although almost all tumor cells express the Fas receptor, the Fas pathway may also be beneficial to tumor cell survival rather than apoptosis. 6,[8][9][10] Activation of Fas signaling in the Lewis lung cancer cell line (3LL cells) does not cause apoptosis but induces 3LL cells to secrete more prostaglandin E2(PGE2).…”

Section: Introductionmentioning

confidence: 99%

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

et al. 2014

View full text Add to dashboard Cite

The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD81 T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.

show abstract

Section: Introductionmentioning

confidence: 99%

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The exosomes secreted by activated human T cells express bioactive FasL and can induce the apoptosis of Jurkat T cells (15). Exosomes purified from CD8 + T cells, which are generated by cultivation of OVA-pulsed dendritic cells (DCs) with naive CD8 + T cells derived from OT-I mice, also express FasL and can inhibit DCs to stimulate CD8 + CTL responses (19). However, the potential effects of FasL in activated T cell exosomes on Fas-resistant tumor cells are not well understood.…”

mentioning

confidence: 99%

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Cai

Yang

et al. 2012

The Journal of Immunology

218

174

View full text Add to dashboard Cite

Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8+ T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape.

show abstract

“…Indeed, in agreement with this role, we noted that the treatment of Exos with anti-CD9 decreased their incorporation by the tumour cells. It must be considered, however, that the treatment of Exo with control antibodies also caused a decrease in Exo incorporation by the cells, as shown in the literature [32], though not as intense.…”

Section: Discussionmentioning

confidence: 91%

“…Actually, CD9, CD81, MHC-class I, T-cell receptors, CD54 and LFA-1 have been shown to affect the uptake of Exos by different cell types [22,25,[32][33][34]. Furthermore, mechanisms involved in this incorporation may vary among cell types and activation status both of target and source cells.…”

Section: Discussionmentioning

confidence: 99%

Tumour Cells Incorporate Exosomes Derived from Dendritic Cells Through a Mechanism Involving the Tetraspanin CD9

Romagnoli

Toniolo

Migliori

et al. 2013

Exosomes microvesicles

View full text Add to dashboard Cite

Exosomes (Exos) are secreted nanovesicles that contain membrane proteins and genetic material, which can be transferred between cells and contribute to their communication in the body. We show that Exos, obtained from mature human dendritic cells (DCs), are incorporated by tumour cells, which after Exos treatment, acquire the expression of HLA-class I, HLA-class II, CD86, CD11c, CD54 and CD18. This incorporation reaches its peak eight hours after treatment, can be observed in different cell tumour lines (SK-BR-3, U87 and K562) and could be a means to transform non-immunogenic into immunogenic tumour cells. Interestingly, tetraspanins, which are expressed by the tumour cells, have their surface level decreased after Exo treatment. Furthermore, the intensity of Exo incorporation by the different tumour cell lines was proportional to their CD9 expression levels and pretreatment of Exos with anti-CD9 decreased their incorporation (by SK-BR-3 cells). This modification of tumour cells by DC-derived Exos may allow their use in new immunotherapeutic approaches to cancer. Furthermore, by showing the involvement of CD9 in this incorporation, we provide a possible selection criterion for tumours to be addressed by this strategy.

show abstract

Dendritic Cells Recruit T Cell Exosomes via Exosomal LFA-1 Leading to Inhibition of CD8+ CTL Responses through Downregulation of Peptide/MHC Class I and Fas Ligand-Mediated Cytotoxicity

Cited by 105 publications

References 49 publications

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Tumour Cells Incorporate Exosomes Derived from Dendritic Cells Through a Mechanism Involving the Tetraspanin CD9

Contact Info

Product

Resources

About