bims-tumime 2024-06-30 papers

bims-tumime

Biomed News

on Tumor microenvironment and metabolism

Issue of 2024–06–30
six papers selected by
Alex Muir, University of Chicago

Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.
Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.
Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.
Regulation of anti-tumor immunity by metal ion in the tumor microenvironment.
Effects of Exercise-Induced Changes in Myokine Expression on the Tumor Microenvironment.
FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

BMB Rep. 2024 Jun 26. pii: 6203. [Epub ahead of print]

Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.

Seon Ah Lim.

Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment (TME). In the TME, numerous distinct factors actively induce immunosuppression, restricting the efficacy of anticancer immune reactions. Recently, metabolic reprogramming of tumors has been recognized for its role in modulating the tumor microenvironment to enhance immune cell responses in the TME. Furthermore, recent elucidations underscore the critical role of metabolic limitations imposed by the tumor microenvironment on the effectiveness of antitumor immune cells, guiding the development of novel immunotherapeutic approaches. Hence, achieving a comprehensive understanding of the metabolic requirements of both cancer and immune cells within the TME is pivotal. This insight not only aids in acknowledging the current limitations of clinical practices but also significantly shapes the trajectory of future research endeavors in the domain of cancer immunotherapy. In addition, therapeutic interventions targeting metabolic limitations have exhibited promising potential as combinatory treatments across diverse cancer types. In this review, we first discuss the metabolic barriers in the TME. Second, we explore how the immune response is regulated by metabolites. Finally, we will review the current strategy for targeting metabolism to not simply inhibit tumor growth but also enhance antitumor immune responses. Thus, we could suggest potent combination therapy for improving immunotherapy with metabolic inhibitors.
Mol Oncol. 2024 Jun 22.

Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.

Josquin Moraly, Taisuke Kondo, Mehdi Benzaoui, Justyn DuSold, Sohan Talluri, Marie C Pouzolles, Christopher Chien, Valérie Dardalhon, Naomi Taylor.

  Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as "living drugs," their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post-translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic-based strategies to enhance T cell immunotherapy.

Keywords:  T cells; anti‐tumor immunotherapy; chimeric antigen receptor; immunometabolism; nutrient transporters; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13691
Cell Host Microbe. 2024 Jun 18. pii: S1931-3128(24)00197-5. [Epub ahead of print]

Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.

Selene Meza-Perez, Mingyong Liu, Aaron Silva-Sanchez, Casey D Morrow, Peter G Eipers, Elliot J Lefkowitz, Travis Ptacek, Christopher D Scharer, Alexander F Rosenberg, Dave D Hill, Rebecca C Arend, Michael J Gray, Troy D Randall.

  Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.

Keywords:  Treg activation; anti-tumor responses; arginine metabolism; gut Proteobacteria; mTOR pathway; omentum

DOI:  https://doi.org/10.1016/j.chom.2024.06.003
Front Immunol. 2024 ;15 1379365

Regulation of anti-tumor immunity by metal ion in the tumor microenvironment.

Yaoxin Gao, Shasha Liu, Yifan Huang, Feng Li, Yi Zhang.

  Metal ions play an essential role in regulating the functions of immune cells by transmitting intracellular and extracellular signals in tumor microenvironment (TME). Among these immune cells, we focused on the impact of metal ions on T cells because they can recognize and kill cancer cells and play an important role in immune-based cancer treatment. Metal ions are often used in nanomedicines for tumor immunotherapy. In this review, we discuss seven metal ions related to anti-tumor immunity, elucidate their roles in immunotherapy, and provide novel insights into tumor immunotherapy and clinical applications.

Keywords:  T cells; metal ions; nanomedicines; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1379365
Sports Med Int Open. 2024 ;8 a22831663

Effects of Exercise-Induced Changes in Myokine Expression on the Tumor Microenvironment.

Nadira Gunasekara, Dorothea Clauss, Wilhelm Bloch.

  In this narrative review, we summarize the direct and indirect effects that myokines have on the tumor microenvironment. We took studies of various cancer types and species into account. Systematic reviews and meta-analyses that matched the search terms were also considered. We searched databases for six months. As a narrative approach was chosen, no data was analyzed or reanalyzed. The goal of this narrative review is to create an overview on the topic to identify research gaps and answer the questions as to whether myokine expression may be relevant in cancer research in regard to the tumor microenvironment. Six commonly known myokines were chosen. We found strong links between the influence exercise has on interleukin-6, oncostatin M, secreted protein acidic and rich in cysteine, and irisin in the context of tumor progression and inhibition via interactions with the tumor microenvironment. It became clear that the effects of myokines on the tumor microenvironment can vary and contribute to disease progression or regression. Interactions among myokines and immune cells must also be considered and require further investigation. To date, no study has shown a clear connection, while multiple studies suggest further investigation of the topic, similar to the effects of exercise on myokine expression.

Keywords:  SPARC; cancer; interleukin-6; irisin; oncostatin-m

DOI:  https://doi.org/10.1055/a-2283-1663
EMBO Mol Med. 2024 Jun 26.

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Nicla Lorito, Angela Subbiani, Alfredo Smiriglia, Marina Bacci, Francesca Bonechi, Laura Tronci, Elisabetta Romano, Alessia Corrado, Dario Livio Longo, Marta Iozzo, Luigi Ippolito, Giuseppina Comito, Elisa Giannoni, Icro Meattini, Alexandra Avgustinova, Paola Chiarugi, Angela Bachi, Andrea Morandi.

  Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

Keywords:  Desaturases; Ferroptosis; Lipid Droplets; Lipid Metabolism; Polyunsaturated Fatty Acids

DOI:  https://doi.org/10.1038/s44321-024-00090-6