bims-tumime 2024-02-18 papers

bims-tumime

Biomed News

on Tumor microenvironment and metabolism

Issue of 2024–02–18
six papers selected by
Alex Muir, University of Chicago

Reprogramming T cell metabolism to enhance adoptive cell therapies.
Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.
Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.
Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer.
Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.
Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring.

Int Immunol. 2024 Feb 14. pii: dxae007. [Epub ahead of print]

Reprogramming T cell metabolism to enhance adoptive cell therapies.

Meghan Kates, Samuel D Saibil.

  Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then re-infusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signaling and presents a metabolically challenging environment that leads to T cell suppression. T cell metabolism is an expanding field of research with a focus on understanding its inherent link to T cell function. Here, we review the current model of T cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T cell performance could contribute to improving therapy efficacy for patients.

Keywords:  Cancer Immunology; Immunometabolism; Immunotherapy

DOI:  https://doi.org/10.1093/intimm/dxae007
Cell Metab. 2024 Feb 08. pii: S1550-4131(24)00012-3. [Epub ahead of print]

Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.

Yongfeng Lai, Yuan Gao, Junhong Lin, Fangfang Liu, Liguo Yang, Jie Zhou, Ying Xue, Yan Li, Zhenzhen Chang, Jing Li, Tengfei Chao, Jing Chen, Xiang Cheng, Xianfu Gao, Xiong Li, Fujia Lu, Qian Chu, Weimin Wang.

  Immunomodulatory effects of long-chain fatty acids (LCFAs) and their activating enzyme, acyl-coenzyme A (CoA) synthetase long-chain family (ACSL), in the tumor microenvironment remain largely unknown. Here, we find that ACSL5 functions as an immune-dependent tumor suppressor. ACSL5 expression sensitizes tumors to PD-1 blockade therapy in vivo and the cytotoxicity mediated by CD8+ T cells in vitro via regulation of major histocompatibility complex class I (MHC-I)-mediated antigen presentation. Through screening potential substrates for ACSL5, we further identify that elaidic acid (EA), a trans LCFA that has long been considered harmful to human health, phenocopies to enhance MHC-I expression. EA supplementation can suppress tumor growth and sensitize PD-1 blockade therapy. Clinically, ACSL5 expression is positively associated with improved survival in patients with lung cancer, and plasma EA level is also predictive for immunotherapy efficiency. Our findings provide a foundation for enhancing immunotherapy through either targeting ACSL5 or metabolic reprogramming of antigen presentation via dietary EA supplementation.

Keywords:  ACSL5; CD8(+) T cell; MHC class I; NLRC5; antigen presentation; checkpoint blockade; elaidic acid; immunotherapy; long-chain fatty acids

DOI:  https://doi.org/10.1016/j.cmet.2024.01.012
bioRxiv. 2024 Feb 02. pii: 2024.01.31.578284. [Epub ahead of print]

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.

Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles G Drake, Drew M Pardoll.

The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

DOI: https://doi.org/10.1101/2024.01.31.578284
Trends Cancer. 2024 Feb 13. pii: S2405-8033(24)00007-4. [Epub ahead of print]

Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer.

Chaitali Khan, Nasser M Rusan.

  Cancer metastasis causes over 90% of cancer patient fatalities. Poor prognosis is determined by tumor type, the tumor microenvironment (TME), organ-specific biology, and animal physiology. While model organisms do not fully mimic the complexity of humans, many processes can be studied efficiently owing to the ease of genetic, developmental, and cell biology studies. For decades, Drosophila has been instrumental in identifying basic mechanisms controlling tumor growth and metastasis. The ability to generate clonal populations of distinct genotypes in otherwise wild-type animals makes Drosophila a powerful system to study tumor-host interactions at the local and global scales. This review discusses advancements in tumor biology, highlighting the strength of Drosophila for modeling TMEs and systemic responses in driving tumor progression and metastasis.

Keywords:  Drosophila; cancer; inflammation; metabolism; metastasis; organ-specific response; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.01.007
Cell Death Dis. 2024 Feb 15. 15(2): 145

Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.

Chenfeng Han, Minmin Ge, Pengfei Xing, Tian Xia, Cangang Zhang, Kaili Ma, Yifu Ma, Shicheng Li, Wenhui Li, Xiaowei Liu, Baojun Zhang, Liyuan Zhang, Lianjun Zhang.

Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.

DOI: https://doi.org/10.1038/s41419-024-06503-1
Sci Adv. 2024 Feb 16. 10(7): eadj1290

Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring.

Yizhuo Wang, Peng Lou, Yijing Xie, Shuyun Liu, Lan Li, Chengshi Wang, Dan Du, Younan Chen, Yanrong Lu, Jingqiu Cheng, Jingping Liu.

Extracellular vesicle (EV)-based immunotherapeutics have emerged as promising strategy for treating diseases, and thus, a better understanding of the factors that regulate EV secretion and function can provide insights into developing advanced therapies. Here, we report that nutrient availability, even changes in individual nutrient components, may affect EV biogenesis and composition of immune cells [e.g., macrophages (Mφs)]. As a proof of concept, EVs from M1-Mφ under glutamine-depleted conditions (EVGLN-) had higher yields, functional compositions, and immunostimulatory potential than EVs from conventional GLN-present medium (EVGLN+). Mechanistically, the systemic metabolic rewiring (e.g., altered energy and redox metabolism) induced by GLN depletion resulted in up-regulated pathways related to EV biogenesis/cargo sorting (e.g., ESCRT) and immunostimulatory molecule production (e.g., NF-κB and STAT) in Mφs. This study highlights the importance of nutrient status in EV secretion and function, and optimizing metabolic states and/or integrating them with other engineering methods may advance the development of EV therapeutics.

DOI: https://doi.org/10.1126/sciadv.adj1290