Abstract
BackgroundChanges in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD).MethodsWe used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo.ResultsGBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+ T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo.ConclusionsGBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8+ T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.
Highlights
Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment
glycogen branching enzyme (GBE1) prevents CCL5 and CXCL10 expression in lung adenocarcinoma (LUAD) cells Increasing evidence indicates that changes in glycogen metabolism of cancer cells are emerging in response to the tumor microenvironment [2]
We demonstrated that the supernatants derived from GBE1 knockdown cells or those treated with recombinant human CCL5 and CXCL10 robustly enhanced the recruitment of CD8+ T lymphocytes; the neutralizing antibodies for CCL5 or CXCL10 significantly hampered the cell migration induced by shRNA-mediated knockdown of GBE1 (shGBE1) cell supernatants (Fig. 2c, d)
Summary
Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In addition to tumor cells, the tumor microenvironment harbors a variety of host-derived cells. Based on previous studies conducted by us and the others, a large number of tumor-infiltrating lymphocytes (TILs) correlates with increased expression of multiple chemokines CCL5 and CXCL10, capable of recruiting effector T cells, by attracting CD8+ T lymphocytes into various tumors [6,7,8,9,10]. PD-L1 expression on tumor cells and its presence in the tumor microenvironment correlates negatively with the presence of TILs. When PD-L1 is present on the cancer cells, and macrophages bind to programmed cell death protein-1 (PD-1) on activated cytotoxic T lymphocytes (CTLs) at the tumor site, PD-L1-induced inhibitory signal shuts down their anti-tumor activity [12]. To elucidate whether PD-L1 expression reflects host-tumor immunity, we evaluated CD8+ TILs, since the presence of particular TIL subsets correlates with better prognosis in cutaneous melanoma, colorectal cancer, esophageal cancer, renal cancer, and ovarian cancer [15,16,17,18,19,20,21]
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