bims-stacyt 2022-12-11 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–12–11
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Diverse effects of obesity on antitumor immunity and immunotherapy.
Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.
Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer.
The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli.
Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma.
Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells.
Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity.
BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1.

Trends Mol Med. 2022 Dec 03. pii: S1471-4914(22)00294-5. [Epub ahead of print]

Diverse effects of obesity on antitumor immunity and immunotherapy.

Lydia Dyck, Lydia Lynch.

  Currently, obesity is one of the biggest health burdens facing society because it causes several comorbidities, such as type 2 diabetes, atherosclerosis, and heart disease. Obesity is also linked to multiple types of cancer. Obesity is the second most common preventable cause of cancer after smoking; the rates of obesity are increasing worldwide, as are the rates of obesity-associated cancer. Multiple factors link obesity to cancer, such as increased levels of growth hormones and adipokines, gut dysbiosis, altered tumor metabolism, and chronic low-grade inflammation. More recently, obesity has been shown to also affect the immune response against cancer. In this review we discuss the interplay between obesity, the immune system, and cancer.

Keywords:  antitumor immunity; cancer; immunometabolism; immunotherapy; obesity

DOI:  https://doi.org/10.1016/j.molmed.2022.11.004
Adv Sci (Weinh). 2022 Dec 07. e2204808

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Junlong Zhao, Zhimin Tian, Shoujie Zhao, Dayun Feng, Zhixiong Guo, Liangzhi Wen, Yejing Zhu, Fenghua Xu, Jun Zhu, Shouzheng Ma, Jie Hu, Tao Jiang, Yongquan Qu, Dongfeng Chen, Lei Liu.

  Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Keywords:  catalysis; immunotherapy; lactate; metabolism; tumor

DOI:  https://doi.org/10.1002/advs.202204808
J Cancer Res Clin Oncol. 2022 Dec 06.

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer.

Green Hong, Pureum Sun, Chaeuk Chung, Dongil Park, Song-I Lee, Nayoung Kim, Seong Eun Lee, Jeong Eun Lee, Yea Eun Kang, Da Hyun Kang.

   PURPOSE: Although increased plasma growth differentiation factor-15 (GDF15) levels have been reported in patients with various cancers, the predictive role of PD-1/PD-L1 inhibitors in advanced cancers remains unknown. This study aimed to investigate GDF15 levels as a predictive marker in advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors and analyze their association with immune cell populations.
METHODS: This study included 87 patients with advanced NSCLC receiving anti-PD-1/PD-L1 inhibitors between March 2018 and May 2020. Blood samples were obtained immediately before and months after PD-1/PD-L1 inhibitor administration.
RESULTS: The objective response rate (ORR) was significantly higher in the low GDF15 than in the high GDF15 group (39.2% vs. 15.3%, P = 0.013). The median progression-free survival (PFS) was significantly longer in the low GDF15 than in the high GDF15 group (13.2 [95% CI 7.6-18.9] vs. 7.2 [95% CI 4.8-9.6] months, P = 0.048). Moreover, plasma GDF15 levels negatively correlated with PD-1+/CD8+ T cells (r = - 0.399, P = 0.003) and positively with PD-1+/Treg cells (r = 0.507, P < 0.001) and PD-1+Treg/CD4+ T cells (r = 0.439, P < 0.001). The ORR was significantly higher in the group with decreased GDF15 from baseline than in the increased GDF15 group (37.2% vs. 10.0%, P = 0.026). The median PFS was significantly longer in the decreased GDF15 group (14.8 [95% CI 10.4-19.2] vs. 5.9 [95% CI 2.8-9.0] months, P = 0.002). Plasma GDF15 levels were associated with PD-1+CD8+ T cells and PD-1+ Treg cells.
CONCLUSION: Plasma GDF15 could be a potential biomarker for predicting the efficacy and survival benefit of immunotherapy in advanced NSCLC.

Keywords:  Biomarker; Efficacy; GDF15; Immunotherapy; Non-small cell lung cancer; Survival

DOI:  https://doi.org/10.1007/s00432-022-04500-5
mBio. 2022 Dec 08. e0306822

The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli.

Bevin C English, Hannah P Savage, Scott P Mahan, Vladimir E Diaz-Ochoa, Briana M Young, Basel H Abuaita, Gautam Sule, Jason S Knight, Mary X O'Riordan, Andreas J Bäumler, Renée M Tsolis.

  Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the endoplasmic reticulum (ER) stress sensor Inositol-requiring enzyme 1 alpha (IRE1α) and its downstream transcription factor X box binding protein 1 (XBP1) enhance the upregulation of glycolysis in classically activated macrophages (CAMs). The IRE1α-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by lipopolysaccharide (LPS) stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1α activation; while Toll-like receptor 4 (TLR4) supports glycolysis under both conditions, TLR4 is required for activation of IRE1α in response to LPS treatment but not B. abortus infection. Though IRE1α and XBP1 are necessary for maximal induction of glycolysis in CAMs, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cell's metabolic response and that IRE1α activation may be a way to fine-tune metabolic reprogramming. IMPORTANCE The immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1α, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1α by independent mechanisms. While the IRE1α-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1α and XBP1 in innate immunity.

Keywords:  Brucella; endoplasmic reticulum; immunometabolism; innate immunity

DOI:  https://doi.org/10.1128/mbio.03068-22
Front Oncol. 2022 ;12 1057930

Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma.

Ying-Chun Yu, Azaj Ahmed, Hsueh-Chou Lai, Wei-Chung Cheng, Juan-Chern Yang, Wei-Chun Chang, Lu-Min Chen, Yan-Shen Shan, Wen-Lung Ma.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.

Keywords:  cachexia; endocrine organ-like tumour (EOLT); muscle wasting; pancreatic ductal adenocarcinoma (PDAC); tissue wasting

DOI:  https://doi.org/10.3389/fonc.2022.1057930
Cell Syst. 2022 Dec 01. pii: S2405-4712(22)00462-8. [Epub ahead of print]

Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells.

Kshitiz, Junaid Afzal, Yasir Suhail, Hao Chang, Maimon E Hubbi, Archer Hamidzadeh, Ruchi Goyal, Yamin Liu, Peng Sun, Stefania Nicoli, Chi V Dang, Andre Levchenko.

  Response to hypoxia is a highly regulated process, but little is known about single-cell responses to hypoxic conditions. Using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity in various cancer cell lines and patient-derived cancer cells, we show that hypoxic responses in individual cancer cells can be highly dynamic and variable. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, implicating reactive-oxygen-species-dependent chaperone-mediated autophagy of HIF-1α in a subset of cells. Furthermore, we show that oscillatory response is modulated by the abundance of extracellular lactate in a quorum-sensing-like mechanism. We show that oscillatory HIF-1α activity rescues hypoxia-mediated inhibition of cell division and causes broad suppression of genes downregulated in cancers and activation of genes upregulated in many cancers, suggesting a mechanism for aggressive growth in a subset of hypoxic tumor cells.

Keywords:  HIF; ROS; Warburg and reverse Warburg effect; cancer microenvironment; chaperone-mediated autophagy; hypoxia; hypoxic oscillations; lactate; quorum sensing; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cels.2022.11.003
Front Immunol. 2022 ;13 1004644

Influence of nutrients and metabolites on the differentiation of plasma cells and implications for autoimmunity.

Bandik Föh, Jana Sophia Buhre, Christian Sina, Marc Ehlers.

  The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.

Keywords:  IL-10; IgG glycosylation; antibodies; autoimmunity; metabolism; metabolites; nutrients; plasma cells

DOI:  https://doi.org/10.3389/fimmu.2022.1004644
iScience. 2022 Dec 22. 25(12): 105626

BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1.

Robert Hromas, Gayathri Srinivasan, Ming Yang, Aruna Jaiswal, Taylor A Totterdale, Linda Phillips, Austin Kirby, Nazli Khodayari, Mark Brantley, Elizabeth A Williamson, Kimi Y Kong.

  Tumors with BRCA1 mutations have poor prognoses due to genomic instability. Yet this genomic instability has risks and BRCA1-deficient (def) cancer cells must develop pathways to mitigate these risks. One such risk is the accumulation of unfolded proteins in BRCA1-def cancers from increased mutations due to their loss of genomic integrity. Little is known about how BRCA1-def cancers survive their genomic instability. Here we show that BRCA1 is an E3 ligase in the endoplasmic reticulum (ER) that targets the unfolded protein response (UPR) stress sensors, Eukaryotic Translation Initiation Factor 2-alpha Kinase 3 (PERK) and Serine/Threonine-Protein Kinase/Endoribonuclease Inositol-Requiring Enzyme 1 (IRE1) for ubiquitination and subsequent proteasome-mediated degradation. When BRCA1 is mutated or depleted, both PERK and IRE1 protein levels are increased, resulting in a constitutively activated UPR. Furthermore, the inhibition of protein folding or UPR signaling markedly decreases the overall survival of BRCA1-def cancer cells. Our findings define a mechanism used by the BRCA1-def cancer cells to survive their increased unfolded protein burden which can be used to develop new therapeutic strategies to treat these cancers.

Keywords:  Cancer; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2022.105626