bims-mecami 2023-07-09 papers

Issue of 2023–07–09
five papers selected by
Oltea Sampetrean, Keio University

Trends Cancer. 2023 Jul 01. pii: S2405-8033(23)00104-8. [Epub ahead of print]

Diet, nutrient supply, and tumor immune responses.

Claire L McIntyre, Ayantu Temesgen, Lydia Lynch.

Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies.

Keywords: T cells; cancer; diet; immune cells; metabolism; obesity

DOI: https://doi.org/10.1016/j.trecan.2023.06.003

Nature. 2023 Jul 05.

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.

Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, Hongbo Chi.

Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.

DOI: https://doi.org/10.1038/s41586-023-06299-8

bioRxiv. 2023 May 31. pii: 2023.05.29.542774. [Epub ahead of print]

Human plasma-like medium facilitates metabolic tracing and enables upregulation of immune signaling pathways in glioblastoma explants.

Mohamad El Shami, Milan R Savani, Lauren C Gattie, Bailey Smith, William H Hicks, Jeremy N Rich, Timothy E Richardson, Samuel K McBrayer, Kalil G Abdullah.

Purpose: Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical to the study of tumor metabolism. Cell culture models of this disease are not routinely cultured under physiologically relevant nutrient conditions and do not retain cellular heterogeneity present in the parental TME. Moreover, in vivo, stable isotope tracing in intracranial glioma xenografts, the gold standard for metabolic investigation, is time consuming and technically challenging. To provide insights into glioma metabolism in the presence of an intact TME, we performed stable isotope tracing analysis of patient-derived, heterocellular Surgically eXplanted Organoid (SXO) glioma models in human plasma-like medium (HPLM).
Methods: Glioma SXOs were established and cultured in conventional media or transitioned to HPLM. We evaluated SXO cytoarchitecture and histology, then performed spatial transcriptomic profiling to identify cellular populations and differential gene expression patterns. We performed stable isotope tracing with 15 N 2 -glutamine to evaluate intracellular metabolite labeling patterns.
Results: Glioma SXOs cultured in HPLM retain cytoarchitecture and cellular constituents. Immune cells in HPLM-cultured SXOs demonstrated increased transcription of immune-related signatures, including innate immune, adaptive immune, and cytokine signaling programs. 15 N isotope enrichment from glutamine was observed in metabolites from diverse pathways, and labeling patterns were stable over time.
Conclusion: To enable ex vivo, tractable investigations of whole tumor metabolism, we developed an approach to conduct stable isotope tracing in glioma SXOs cultured under physiologically relevant nutrient conditions. Under these conditions, SXOs maintained viability, composition, and metabolic activity while exhibiting increased immune-related transcriptional programs.

DOI: https://doi.org/10.1101/2023.05.29.542774

Cell Metab. 2023 Jun 28. pii: S1550-4131(23)00215-2. [Epub ahead of print]

Immunometabolic coevolution defines unique microenvironmental niches in ccRCC.

Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.

Keywords: cancer metabolism; immune microenvironment; immunometabolism; imputation; intratumoral heterogeneity; metabolites; metabolomics; renal cell carcinoma; transcriptomics

DOI: https://doi.org/10.1016/j.cmet.2023.06.005

Neuro Oncol. 2023 Jul 03. pii: noad117. [Epub ahead of print]

Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.

Evan K Noch, Laura N Palma, Isaiah Yim, Nayah Bullen, Yuqing Qiu, Hiranmayi Ravichandran, Junbum Kim, Andre Rendeiro, Melissa B Davis, Olivier Elemento, David J Pisapia, Kevin Zhai, H Carl LeKaye, Jason A Koutcher, Patrick Y Wen, Keith L Ligon, Lewis C Cantley.

BACKGROUND: Insulin feedback is a critical mechanism responsible for poor clinical efficacy of PI3K inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma. We investigated combination anti-hyperglycemic therapy in a mouse model of glioblastoma and evaluated the association of glycemic control in clinical trial data from patients with glioblastoma.
METHODS: The effect of the anti-hyperglycemic regimens metformin and the ketogenic diet were evaluated in combination with PI3K inhibition in patient-derived glioblastoma cells and an orthotopic glioblastoma mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent glioblastoma.
RESULTS: We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves treatment efficacy in an orthotopic glioblastoma xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with glioblastoma. We also found that PI3K inhibition increased insulin receptor activation and T cell and microglia abundance in tumor tissue from these patients.
CONCLUSION: Reducing insulin feedback improves the efficacy of PI3K inhibition in glioblastoma in mice, and hyperglycemia worsens progression-free survival in patients with glioblastoma treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in glioblastoma and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in glioblastoma patients.

Keywords: Glioblastoma; hyperglycemia; insulin; metformin; phosphatidylinositol 3-kinase

DOI: https://doi.org/10.1093/neuonc/noad117