Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma

Gähler, Alexander; Trufa, Denis I.; Chiriac, Mircea T.; Tausche, Patrick; Hohenberger, Katja; Brunst, Ann-Kathrin; Rauh, Manfred; Geppert, Carol I.; Rieker, Ralf J.; Krammer, Susanne; Leberle, Anna; Sı̂rbu, Horia; Hartmann, Andréas; Finotto, Susetta

doi:10.3389/fonc.2022.873293

Cited by 10 publications

(9 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Under glucose-deprived conditions, a decrease in cell count was evident after 48 hours in 5mM SB, as well as in comparison with 1 to 5mM SB ( Figure 1C ). The results in Figure 1C also show distinct growth restriction caused by glucose deprivation, which we described previously ( 14 ), resulting in a reduced cell count after 48 and 72h in the absence of SB stimulation. The addition of 5mM SB resulted in a further reduced average percentage of cell count in the absence of glucose.…”

Section: Resultssupporting

confidence: 86%

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo

Thome,

Tausche,

Hohenberger

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

BackgroundDespite therapy advances, one of the leading causes of cancer deaths still remains lung cancer. To improve current treatments or prevent non-small cell lung cancer (NSCLC), the role of the nutrition in cancer onset and progression needs to be understood in more detail. While in colorectal cancer, the influence of local microbiota derived SCFAs have been well investigated, the influence of SCFA on lung cancer cells via peripheral blood immune system should be investigated more deeply. In this respect, nutrients absorbed via the gut might affect the tumor microenvironment (TME) and thus play an important role in tumor cell growth.ObjectiveThis study focuses on the impact of the short-chain fatty acid (SCFA) Sodium Butyrate (SB), on lung cancer cell survival. We previously described a pro-tumoral role of glucose on A549 lung adenocarcinoma cell line. In this study, we wanted to know if SB would counteract the effect of glucose and thus cultured A549 and H520 in vitro with and without SB in the presence or absence of glucose and investigated how the treatment with SB affects the survival of lung cancer cells and its influence on immune cells fighting against lung cancer.MethodsIn this study, we performed cell culture experiments with A549, H520 and NSCLC-patient-derived epithelial cells under different SB levels. To investigate the influence on the immune system, we performed in vitro culture of peripheral mononuclear blood cells (PBMC) from control, smoker and lung cancer patients with increasing SB concentrations.ResultsTo investigate the effect of SB on lung tumor cells, we first analyzed the effect of 6 different concentrations of SB on A549 cells at 48 and 72 hours cell culture. Here we found that, SB treatment reduced lung cancer cell survival in a concentration dependent manner. We next focused our deeper analysis on the two concentrations, which caused the maximal reduction in cell survival. Here, we observed that SB led to cell cycle arrest and induced early apoptosis in A549 lung cancer cells. The expression of cell cycle regulatory proteins and A549 lung cancer stem cell markers (CD90) was induced. Additionally, this study explored the role of interferon-gamma (IFN-γ) and its receptor (IFN-γ-R1) in combination with SB treatment, revealing that, although IFN-γ-R1 expression was increased, IFN-γ did not affect the efficacy of SB in reducing tumor cell viability. Furthermore, we examined the effects of SB on immune cells, specifically CD8+ T cells and natural killer (NK) cells from healthy individuals, smokers, and NSCLC patients. SB treatment resulted in a decreased production of IFN-γ and granzyme B in CD8+ T cells and NK cells. Moreover, SB induced IFN-γ-R1 in NK cells and CD4+ T cells in the absence of glucose both in PBMCs from controls and NSCLC subjects.ConclusionOverall, this study highlights the potential of SB in inhibiting lung cancer cell growth, triggering apoptosis, inducing cell cycle arrest, and modulating immune responses by activating peripheral blood CD4+ T cells while selectively inducing IFN-γ-R1 in NK cells in peripheral blood and inhibiting peripheral blood CD8+ T cells and NK cells. Thus, understanding the mechanisms of action of SB in the TME and its influence on the immune system provide valuable insights of potentially considering SB as a candidate for adjunctive therapies in NSCLC.

show abstract

Section: Resultssupporting

confidence: 86%

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo

Thome,

Tausche,

Hohenberger

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…One problem is nutrition which can be imbalanced and thus might support the tumor growth 37,38 . We recently reported our investigation on the role of blood glucose in our cohort of patients with LUAD 4 . Other studies also demonstrated that glucose restriction in the diet resulted in decreased tumor development in a murine model of lung cancer 4,39 .…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported our investigation on the role of blood glucose in our cohort of patients with LUAD 4 . Other studies also demonstrated that glucose restriction in the diet resulted in decreased tumor development in a murine model of lung cancer 4,39 . Following up this observation, we asked about the role of lipids in the same cohort of patients with LUAD 3 .…”

Section: Discussionmentioning

confidence: 99%

“…At this regard, a preventive intervention through regulation of the nutrition of the patients with lung cancer is gaining much attention 3 . We recently demonstrated that reducing dietary carbohydrate intake might affect tumor growth, improve current immunotherapy, and target tumor immune escape caused by glucose levels in the tumor microenvironment 4 . In that study, we analyzed a cohort of patients with lung adenocarcinoma (LUAD), a major histologic subtype of non-small-cell lung cancer (NSCLC).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression

Hartmann

Trufa

Hohenberger

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung’s tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells.

show abstract

“…Conversely, blockade of lactate production via inhibition of pyruvate dehydrogenase with oxamate led to increased CD8+ T cell infiltration, reduced NSCLC tumor growth and improved responses to anti-PD-1 antibodies [99]. In line with this, a recent report showed how a glucose-restricted diet led to reduced tumor growth and increased intratumoral infiltration of CD8 effector memory T cells and NK cells [100].…”

Section: Lactatementioning

confidence: 78%

Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer

Otegui

Houry

Arozarena

et al. 2023

Cancers

View full text Add to dashboard Cite

Despite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs). Mutations in KRAS, SKT11(LKB1), KEAP1 and TP53 and co-mutations of these genes are the main determinants of ICI response in non-small-cell lung cancer (NSCLC) patients. Recent insights into metabolic changes in cancer cells that impose restrictions on cytotoxic T cells and the efficacy of ICIs indicate that targeting such metabolic restrictions may favor therapeutic responses. Other emerging pathways for therapeutic interventions include epigenetic modulators and DNA damage repair (DDR) pathways, especially in small-cell lung cancer (SCLC). Therefore, the many potential pathways for enhancing the effect of ICIs suggest that, in a few years, we will have much more personalized medicine for lung cancer patients treated with immunotherapy. Such strategies could include vaccines and chimeric antigen receptor (CAR) cells.

show abstract

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma

Cited by 10 publications

References 64 publications

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo

Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression

Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer

Contact Info

Product

Resources

About