Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer

Abstract

Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract

Comprehensive Proteomics Analysis Reveals Dynamic Phenotypes of Tumor-Associated Macrophages and Their Precursor Cells in Tumor Progression

“…16,23 The secreted protein Ifi35 had been reported to promote proliferation and cytotoxic activity of both primary CD8 + T cells and CAR-T cells through the PI3K/AKT/mTOR signaling pathway in colorectal cancer. 24 In this study, TRFC and CD36 were upregulated, but Ifi35 was downregulated in tumor progression. These data illustrated that tumor-associated metabolic alteration is another progression-dependent feature of TAMs apart from impaired immune responses.…”

“…For example, the transferrin receptor (TFRC), a transmembrane protein present on the plasma membrane, interacts with transferrin (which is bound to iron) and generally initiates endocytosis . CD36 plays crucial roles in macrophage differentiation and lipid accumulation and supports tumor growth. , The secreted protein Ifi35 had been reported to promote proliferation and cytotoxic activity of both primary CD8 + T cells and CAR-T cells through the PI3K/AKT/mTOR signaling pathway in colorectal cancer . In this study, TRFC and CD36 were upregulated, but Ifi35 was downregulated in tumor progression.…”

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

“…4 J). 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.…”

Transcriptome of plasma exosome identifies a hsa-miR-483-5p/mRNAs network that regulates chemotherapy resistance in locally advanced rectal cancer

“…The above ndings revealed a complex interactive network of miRNA, MAPK signaling pathway, and the pathogenesis and progression of CRC 25 . Apart from the MAPK signaling pathways, the KEGG pathways of EGFR tyrosine kinase inhibitor resistance pathway 27 , Toll-like receptor signaling pathway 28 , VEGF signaling pathway 29 , and mTOR signaling pathway 30 , were also signi cant contributors to the progression of CRC.…”