bims-mecami 2023-08-13 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–08–13
eight papers selected by
Oltea Sampetrean, Keio University

Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.
Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.
Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment.
Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.
Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.
Emerging therapies in cancer metabolism.
Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer.

Am J Physiol Cell Physiol. 2023 Aug 07.

Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.

Priscilla W Tang, Leonard G Frisbie, Nadine Hempel, Lan G Coffman.

  The ovarian cancer tumor microenvironment (TME) consists of a constellation of abundant cellular components, extracellular matrix, and soluble factors. Soluble factors such as cytokines, chemokines, structural proteins, extracellular vesicles, and metabolites are critical means of non-contact cellular communication acting as messengers to convey pro- or anti-tumorigenic signals. Vast advancements have been made in our understanding of how cancer cells adapt their metabolism to meet environmental demands and utilize these adaptations to promote survival, metastasis, and therapeutic resistance. The stromal TME contribution to this metabolic rewiring has been relatively underexplored, particularly in ovarian cancer. Thus, metabolic activity alterations in the TME hold promise for further study and potential therapeutic exploitation. In this review, we focus on the cellular components of the TME with emphasis on: 1) metabolic signatures of ovarian cancer; 2) understanding the stromal cell network and their metabolic crosstalk with tumor cells; and 3) how stromal and tumor cell metabolites alter intratumoral immune cell metabolism and function. Together, these elements provide insight into the metabolic influence of the TME and emphasize the importance of understanding how metabolic performance drives cancer progression.

Keywords:  Ovarian cancer; metabolomics; stroma; tumor microenvironment

DOI:  https://doi.org/10.1152/ajpcell.00588.2022
Cold Spring Harb Perspect Med. 2023 Aug 08. pii: a041530. [Epub ahead of print]

Cancer Metabolism Historical Perspectives: A Chronicle of Controversies and Consensus.

Chi V Dang.

A century ago, Otto Warburg's work sparked the field of cancer metabolism, which has since taken a tortuous path. As evidence accumulated over the decades, consensus views of causes of cancer emerged, whereby genetic and epigenetic oncogenic drivers promoted immune evasion and induced new blood vessels and neoplastic metabolism to support tumor growth. Neoplastic cells abandon social cues of intercellular cooperation, escape tissue confinement, metastasize, and ultimately kill the host. Herein, key milestones in the study of cancer metabolism are chronicled with an emphasis on carbohydrate metabolism. The field began with a cancer cell-autonomous view that has been refined by a richer understanding of solid cancers as growing, immune-suppressive, complex organs comprising different cell types that are nourished by a variety of nutrients and variable amounts of oxygen through abnormal neovasculatures. Based on foundational historical studies, our current understanding of cancer metabolism offers a hopeful outlook for targeting metabolism to enhance cancer therapy.

DOI: https://doi.org/10.1101/cshperspect.a041530
Front Immunol. 2023 ;14 1225948

Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment.

Lu Chen, Yuchen Wang, Qingqing Hu, Yuxi Liu, Xuchen Qi, Zhihua Tang, Haihong Hu, Nengming Lin, Su Zeng, Lushan Yu.

  The tumor microenvironment (TME) is a crucial driving factor for tumor progression and it can hinder the body's immune response by altering the metabolic activity of immune cells. Both tumor and immune cells maintain their proliferative characteristics and physiological functions through transporter-mediated regulation of nutrient acquisition and metabolite efflux. Transporters also play an important role in modulating immune responses in the TME. In this review, we outline the metabolic characteristics of the TME and systematically elaborate on the effects of abundant metabolites on immune cell function and transporter expression. We also discuss the mechanism of tumor immune escape due to transporter dysfunction. Finally, we introduce some transporter-targeted antitumor therapeutic strategies, with the aim of providing new insights into the development of antitumor drugs and rational drug usage for clinical cancer therapy.

Keywords:  cancer therapy; metabolites; the tumor microenvironment; transporters; tumor immune evasion

DOI:  https://doi.org/10.3389/fimmu.2023.1225948
Front Immunol. 2023 ;14 1208870

Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.

Hongxia Tao, Xuansheng Zhong, Anqi Zeng, Linjiang Song.

  Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the "Warburg effect," sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of 'education' by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.

Keywords:  TAMs; immune escape; immunometabolism; lactate; targeted drug delivery

DOI:  https://doi.org/10.3389/fimmu.2023.1208870
Nat Metab. 2023 Aug 07.

Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.

J N Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A Cassel, Christopher M Adams, Richard M Higashi, David A Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N Lane, Teresa W-M Fan, Ji Zhang, Ruoning Wang.

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.

DOI: https://doi.org/10.1038/s42255-023-00856-1
Blood Adv. 2023 Aug 08. pii: bloodadvances.2023010305. [Epub ahead of print]

T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.

Chiara Montironi, Chaja Feige Jacobs, Gaspard Cretenet, Fleur S Peters, Bauke V Schomakers, Michel van Weeghel, Arnon P Kater, Helga Simon-Molas, Eric Eldering.

Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis for T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human PBMCs, we first established a model which recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (PGA-1, CII, Mec-1), but not from other B-cell malignancies, altered T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to OXPHOS. Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening activation, which could be restored by blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after in vivo reduction of the leukemic burden with combination therapy (Venetoclax and Obinutuzumab), restoring T-cell function. In conclusion, we uncover a pseudohypoxic program connected with T cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.

DOI: https://doi.org/10.1182/bloodadvances.2023010305
Cell Metab. 2023 Aug 08. pii: S1550-4131(23)00265-6. [Epub ahead of print]35(8): 1283-1303

Emerging therapies in cancer metabolism.

Yi Xiao, Tian-Jian Yu, Ying Xu, Rui Ding, Yi-Ping Wang, Yi-Zhou Jiang, Zhi-Ming Shao.

Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.

DOI: https://doi.org/10.1016/j.cmet.2023.07.006
Nat Metab. 2023 Aug 10.

Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer.

Yu Wang, Muhan Xu, Jian Sun, Xiaoxiao Li, Huazheng Shi, Xuefeng Wang, Benming Liu, Tao Zhang, Xu Jiang, Liangyu Lin, Qing Li, Yin Huang, Yong Liang, Mingyuan Hu, Fanjun Zheng, Fengyu Zhang, Jian Sun, Yufang Shi, Ying Wang.

The coordination of immunity across organs is fundamental to cancer development and progression. It is well known that the hostile metabolic microenvironment in the tumour is a major obstacle to effective anti-tumour immunity. However, whether metabolic alterations in secondary lymphoid tissues beyond the tumour can affect anti-tumour immunity remains elusive. Using positron-emission tomography-computed tomography, we show that the spleens of humans and mice with breast cancer are metabolically reprogrammed to a glycolytic state. Such an increase in glucose consumption in the spleen primarily occurs in neutrophils generated by extramedullary haematopoiesis and recruitment from the bone marrow. These neutrophils in the white pulp create a glucose-deprived microenvironment, which, in turn, induces T cell anergy by impairing pyruvate kinase M2 and its action on STAT5, thus compromising their anti-tumour activities. Furthermore, CCL9 chemokine produced by splenic stromal cells is central to splenic neutrophil accumulation, and blockade of the CCR1 receptor favours tumour eradication. Thus, neutrophils metabolically influence the spleen microenvironment and control anti-tumour T cell responses.

DOI: https://doi.org/10.1038/s42255-023-00853-4