Tumor-Secreted IFI35 Promotes Proliferation and Cytotoxic Activity of CD8+ T Cells&amp;nbsp;Through PI3K/Akt/mTOR Signaling Pathway in Colorectal Cancer

Li, Peisi; Zhou, Dawang; Chen, Dong-Wen; Cheng, Yi‐Kan; Chen, Yuan; Lin, Yanyun; Lin, Zhen-Sen; Cai, Jiawei; Huang, Wenfeng; Ke, Hao-Xian; Long, Jia-Hui; Zou, Yifeng; Ye, Shu-biao; Lan, Ping

doi:10.2139/ssrn.4178415

Cited by 3 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The KEGG and GSEA analyses revealed certain signaling pathways associated with the tumoricidal immune microenvironment. CD8 + T‐cell proliferation can be induced by the RAGE and PI3K/AKT/mTOR signaling pathways, 25,26 and the relief of cell‐cycle quiescence can enhance immune surveillance 27 . Moreover, the inhibition of Wnt/catenin and thrombin promoted the expansion of CD8 + T cells and reduced tumor‐associated macrophage switching (M1 to M2) 28,29 .…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

Wei,

Li,

Guo

et al. 2023

Cancer

View full text Add to dashboard Cite

BackgroundPenile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)‐associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor–based combination therapy (PCT).MethodsHPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) in the HPV+ and HPV– groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC.ResultsAmong patients receiving first‐line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV– group. Kaplan–Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first‐line setting. However, these advantages of HPV infection were not observed in multi‐line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV‐induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune‐activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues.ConclusionsHPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first‐line PCT because of the possible stimulation of the antitumor immune microenvironment.Plain Language Summary Human papillomavirus (HPV) infection may induce better objective response rate, progression‐free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first‐line programmed cell death protein 1 inhibitor–based combination therapy (PCT) instead of multi‐line PCT. HPV infection‐induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

show abstract

Section: Discussionmentioning

confidence: 99%

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

Wei,

Li,

Guo

et al. 2023

Cancer

View full text Add to dashboard Cite

show abstract

“…4J). Upon activation, naïve CD8 + T cells proliferate and differentiate to generate effector CD8 + T cells, which, in turn, synthesize copious amounts of cytotoxic effector molecules (Granzyme B and Perforin) and inflammatory cytokines (IFN-γ and TNF-α) that kill tumor cells [16]. Compared with the negative controls, Exo RKO−shNC strongly suppressed CD8 + T-cell proliferation (Fig.…”

Section: Entpd2 Is Localized Primarily In Exosomes and Exosomal Entpd...mentioning

confidence: 91%

Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming

Shi,

Ye,

Zhao

et al. 2024

Cell Commun Signal

View full text Add to dashboard Cite

Background Extracellular ATP–AMP–adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell–derived ATPases in the development and progression of colon cancer. Methods Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. Results We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. Conclusion Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP–adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

show abstract

“…The isolation and culture of TILs were referred to the methods of Li et al (22) In brief, CT26 cells were inoculated subcutaneously into C57BL/6 mice (Charles River), and after a duration of two weeks, the mice were subjected to cervical dislocation for euthanasia purposes. Subsequently, the tumor nodules located beneath the skin were surgically excised.…”

Section: Isolation Culture and Activation Of Cd8 + Tilsmentioning

confidence: 99%

“…Interestingly, beyond its direct sway on tumor cells, the intricate PAM signaling pathway exerts a sweeping influence on the activity of T cells that infiltrate the microenvironment of tumors. Evidence underscores the pathway's role in modulating the proliferation and cytotoxic potency of CD8 + TILs (22). Moreover, this signaling network finely tunes the movement of lymphocytes, impacting their migratory behavior.…”

Section: Introductionmentioning

confidence: 99%

MiR-26a-5p exerts its influence by targeting EP300, a molecule known for its role in activating the PI3K/AKT/mTOR signaling pathway in CD8+tumor-infiltrating lymphocytes of colorectal cancer

Chao Wang,

Haonan Lin,

Wangqiang Zhao

et al. 2023

Cell Mol Biol (Noisy-le-grand)

View full text Add to dashboard Cite

Tumor-Secreted IFI35 Promotes Proliferation and Cytotoxic Activity of CD8+ T Cells Through PI3K/Akt/mTOR Signaling Pathway in Colorectal Cancer

Cited by 3 publications

References 34 publications

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming

MiR-26a-5p exerts its influence by targeting EP300, a molecule known for its role in activating the PI3K/AKT/mTOR signaling pathway in CD8+tumor-infiltrating lymphocytes of colorectal cancer

Contact Info

Product

Resources

About