MiR‐15a/16 deficiency enhances anti‐tumor immunity of glioma‐infiltrating CD8+ T cells through targeting mTOR

Abstract

MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR-15a/16 CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared to WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR-15a/16 deficiency resists the exhaustion and maintains the activation of glioma-infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR-15a/16 in tumor-infiltrating immune cells.

AVNP2 protects against cognitive impairments induced by C6 glioma by suppressing tumour associated inflammation in rats

“…The down-regulation of inflammation-related proteins in peri-tumour tissue may be the reason for inhibition of TAMs by AVNP2, which are recruited by gliomas. However, it couldn't function as a protector in humans and secretes inflammatory cytokines to promote tumour cell proliferation inversely (Yang et al, 2017). Hwang JS et al considered that IL-6, TNF-α, iNOS and COX-2 were glioma-secreted soluble factors that could stimulate the activation of TAMs (Hwang et al, 2016).…”

ISG20 promotes local tumor immunity and contributes to poor survival in human glioma

“…However, the associated molecular mechanisms remain poorly understood, and thus more extensive research in this area could provide insight toward improved diagnosis and treatment. [22][23][24][25] Toward this end, we have identified that ISG20 may play a key role in mediating the IDH-related immune response in the glioma microenvironment. The ISG20 gene, located at chromosome 15q26.1, encodes a 20-kDa protein.…”

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…The miRNA cluster miR-15a/16 is localized at chromosome 13q14, and it plays an immune regulatory role in both physiological and inflammatory conditions [57]. The aberrant expression of miR-15 and -16 was initially demonstrated in patients with chronic lymphocytic leukemia, then extended to several types of solid tumors such as prostate cancer and gliomas [58].…”

“…The aberrant expression of miR-15 and -16 was initially demonstrated in patients with chronic lymphocytic leukemia, then extended to several types of solid tumors such as prostate cancer and gliomas [58]. The downregulated expression of miR-15a/16 in CD8+ T cells resulted in low expression of PD-1 in addition to high activity as evidenced by boosted proliferation and production of cytokines such as IFN-c, interleukin-2 (IL-2), and TNF-a [57]. The deficiency of miR-15a/16 inhibited tumor expansion and prolonged the survival in a mouse model of glioma [57].…”

“…The downregulated expression of miR-15a/16 in CD8+ T cells resulted in low expression of PD-1 in addition to high activity as evidenced by boosted proliferation and production of cytokines such as IFN-c, interleukin-2 (IL-2), and TNF-a [57]. The deficiency of miR-15a/16 inhibited tumor expansion and prolonged the survival in a mouse model of glioma [57]. T-cell exhaustion is a condition of poor T-cell effector function that occurs in various chronic infections and in cancer as a result of sustained expression of inhibitory receptors [1].…”