[Xf Acad9 32 Bits Keygen Torrent
Amancio Mccrae
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Glioblastoma multiforme (GBM) is the most aggressive brain cancer in adults with the worst prognosis. Radiotherapy (RT) and/or chemotherapy with surgery are the major therapeutic modalities in control of GBM growth. However, the overall survival of GBM patients remains very low as 14.6 months with only about 5.6% 5-year survival rate1,2,3. Encouragingly, clinical benefits of combined radiation/immunotherapy (radioimmunotherapy) are evidenced in an array of solid tumors including GBM4,5,6. Promisingly, the tumor immunogenicity potentially enhanced by RT (the Abscopal Effect) and/or radiation-induced molecules with latent immunomodulatory functions are increasingly identified in radiation-treated tumors7,8, both of which are believed to contribute to the synergetic cancer control by radioimmunotherapy. However, in addition to such radiation-associated tumor response to immunotherapy, tumor microenvironment may also acquire resistance to immunotherapy under radiation9, compromising the effectiveness of immune cell facilitated attacks on tumor cells10,11. Thus, for further validating and improving the efficacy of the combined modality, in addition to continuing on the elucidation of the radiation-induced immune attackable molecules, potential radiation-associate immune-cold status, especially in the recurrent and resistant tumors, is to be identified.
Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured by increased glycolysis in solid tumors including GBM12. However, flexible metabolic dynamics is demonstrated in mammalian cells under genotoxic stresses13,14. The oxidative respiration in mitochondria can be instantaneously adjusted in mammalian cells to meet the energy consumption for fueling cell cycle progression and DNA repair15,16. Recently we found that burning the saturated fat (i.e., palmitates in diet) by mitochondrial fatty acid oxidation (FAO) improves mitochondrial homeostasis17. Accumulating new evidence also indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating oxidative phosphorylation (OXPHOS) to meet the increasing cellular fuel demand for repairing and surviving the genotoxic anticancer treatments18,19. Such bioenergetic flexibility appears to fit well into the increased capacity of tumors for metastasis20,21,22, in which the fatty acid (FA) is an alternative critical energy resource to meet the high-fuel consumption in aggressively growing cancer cells23,24,25. FAO is shown to play a critical step for mitochondrial lipid digestion that enhances GBM metabolism26,27, and targeting purine metabolism or NADPH biosynthesis increases the efficacy of GBM control28,29. Recently, two groups further reveal that FA metabolism accelerates the incidence of breast cancer brain metastasis30 and that glycolysis is a less-essential uptake for GBM metabolism31. However, it is unknown whether the enhanced FA metabolism in tumor cells including the recurrent and radioresistant GBM can generate or boost an immunosuppressive status leading to the aggressive behavior with immune evasion.
CD47 is a well-defined immune checkpoint receptor protecting cells from the phagocytotic elimination by immune cells including macrophages via engagement of SIRPα on cell surface32,33. Therapeutic benefits by targeting CD47 are demonstrated in a series of pre-clinical and clinical studies in an array of human cancers34,35,36,37 including GBM treated with radiation and anti-CD47 antibody38, and CD47 is overexpressed in radioresistant breast cancer cells37. Using radioresistant GBM cells, regrown syngeneic mouse GBM, and recurrent tumors of GBM patients, this study reveals an immune evasion function of radioresistant GBM cells through FAO metabolism boosted CD47 anti-phagocytosis. CD47 transcription is activated via FAO-derived acetyl-CoA that acetylates RelA K310 to upregulate CD47 transcription. Blocking FAO not only inhibits aggressive growth of radioresistant GBM cells but diminishes the orthotopically regrown mouse tumors by RT combined with anti-CD47 antibody. Blocking the acetyl-CoA-CD47 pathway is a potential therapeutic approach to sensitize radioresistant tumors to CD47 immunotherapy.
Fundamental mechanisms driving aggressive growth in the resistant and recurrent malignancy with life-threatening conditions remain as the major challenge in GBM treatment, although many milestones have been covered in improving the efficacy of treatment for other cancers. Using radioresistant cells and orthotopic regrown GBM, the present study uncovers an anti-phagocytotic feature in recurrent GBM due to FAO-regulated CD47 expression. The glioblastoma stem cell (GSC)-enriched RR GBM cells are able to rewire the basal glycolysis-dominant metabolism to FAO-centered pathway which functions not only to fuel the cellular energy consumption demand for aggressive tumor growth but also, coordinatively, to defend the resistant cancer cells from macrophage-mediated phagocytosis. Such an alliance of FA-driven aggressive proliferation protected by CD47 anti-phagocytosis illustrates a unique survival advantage in the recurrent GBM cells. Thus, blocking the FAO-CD47 axis may eliminate the resistant cancer cells equipped with a boosted cellular energy fuel supply and CD47-mediated protection against macrophagic attack.
The FAO-mediated CD47 expression may contribute to the overall tumor adaptive (acquired) resistance with the feature of aggressive growth and anti-phagocytosis. A recent study demonstrates that CD47 knockout aggravates the lipid accumulation in normal liver cells60 supporting tight coordination between FAO and CD47 expression. Among the potential key elements responsible for FAO-regulated CD47 expression, FAO-enhanced citrate level is shown to activate the CD47 promoter for gene transcription, thus functioning as the bridging factor between reprogrammed FA metabolism and CD47-mediated immune-escaping ability (Fig. 8c). The argument could be that the acetyl-CoA can also be generated by glycolysis in tumor cells. However, with the significantly lowered glycolysis in the RR GBM cells, it is likely that most cytoplasmic acetyl-CoA is resulted from FAO-derived citrates to form acetyl-CoA catalyzed by ACLY. In addition, acetyl-CoA is well defined to regulate fundamental cellular functions via protein lysine acetylation61,62,63 including the prosurvival lipogenesis and DNA synthesis64,65,66. Indeed, NF-κB RelA K310 acetylation and CD47 promoter activity enhanced by acetyl-CoA were blocked by inhibition of ACYL with SB204990. Interestingly, predicted KAT-specific acetylation sites were also identified in the CD47 protein sequence and indeed, acetyl-CoA mediated CD47 acetylation demonstrated a reduced protein degradation (Supplementary Fig. 8). Therefore, the overall status of FAO-generated metabolic rewiring can activate multiple layers of signaling pathways for prosurvival and immune escaping in the GBM cells surviving radiotherapy. Further definition of the FAO metabolites that regulate other immune checkpoint and/or immune regulating factors will be a significant advance in revealing the dynamic immunosuppressive status in tumor microenvironment under radiotherapy. This study also suggests that tumors resided in a lipid-enriched microenvironment such as GBM and breast cancer brain metastasis, CD47-mediated immunosuppressive status could be readily adopted by the tumor cells via rewiring FA combustion with aggressive growth and immune evasion. However, in addition to citrate converted acetyl-CoA, other FAO-derived metabolic intermediates could also be involved in the checkpoint gene regulation including NADPH and reactive oxygen species (ROS), both have been identified in FAO-dominant cells and required for de-novo lipogenesis in promoting cancer growth67,68.
It is worthy of noticing that radiation can enhance GBM response to anti-CD47 antibody38. It is thus highly possible that in addition to damage-associated molecular patterns (DAMPs), the radiation-induced FAO-CD47 axis may at least in part lead to the synergistic efficacy enhancing the CD47-expressing cells for being targeted by the therapeutic antibodies. The effective tumor control by CD47 immunotherapy is being increasingly demonstrated. Untangling the FA-mediated tumor immune evasion function may help to elucidate the mechanistic insights between irradiated tumor cells and the infiltrated immune cells. However, the FAO-boosted CD47 overexpression although beneficial for enhancing tumor response to targeted antibody, may cause adverse effects including raising the threshold of antibody concentration for eliminating tumor cells and exhaustion of the infiltrated immune cells. We thus assume that a cluster of immunosuppressive genes including CD47 is involved in the adaptive immunotolerance responsive to genotoxic anti-tumor modalities, which is related to the immune evasion and metastasis due to adaptive response in treated tumors84,85. Radiation-induced metabolic rewiring may also be affected by radiation quality including the tumor-delivered dose and time86. Compared to high doses of radiation, lower doses of radiation are shown to induce high tumor immunogenicity and tumor response87 or to increase the molecules of DAMPs required for enhancing immune attack to tumor cells88. Therefore, elucidating the multiple communications between treated tumor cells and host immune surveillance will provide valuable information for inventing effective targets in the combined modality of radiation with immunotherapy.
In conclusion, this study reveals that glycolysis to FAO rewiring in radioresistant GBM cells can boost aggressive growth with CD47-mediated immune evasion via FAO-enhanced acetyl-CoA. Such FAO-driven intrinsic growth potential synchronized with the evasion to extrinsic immune cell attacks is identified in radioresistant GBM cells and recaptured in mouse regrown tumors and clinically treated tumors. This harmonic prosurvival coordination between lipid metabolic dynamics and the anti-phagocytotic function represents a highly flexible adaptive capacity of tumor cells under genotoxic conditions, also highlighting a vital role of metabolic rewiring in the immune-escaping ability of tumor cells. The FAO-CD47 axis is a potential target to eliminate the radioresistant and anti-phagocytotic tumor cells in GBM radioimmunotherapy.
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