CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation

Beckermann, Kathryn E.; Hongo, Rachel; Ye, Xiang; Young, Kirsten; Carbonell, Katie; Healey, Diana C Contreras; Siska, Peter J.; Barone, Sierra; Roe, Caroline E.; Smith, Christof C.; Vincent, Benjamin G.; Mason, Frank M.; Irish, Jonathan M.; Rathmell, W. Kimryn; Rathmell, Jeffrey C.

doi:10.1172/jci.insight.138729

Cited by 62 publications

(56 citation statements)

References 50 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly to the lungs, the observed inflammatory profile suggests an environment where T cells and NK are activated. Their migration into lung or kidney tissue may be responsible for the induction of organ dysfunction (68). Our study suggests potential investigative targets, but the question of their causation in organ failure during COVID-19 is yet to be established.…”

Section: Discussionmentioning

confidence: 92%

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics

et al. 2021

View full text Add to dashboard Cite

Identification of novel immune biomarkers to gauge the underlying pathology and severity of COVID-19 has been difficult due to the lack of longitudinal studies. Here, we analyzed serum collected upon COVID-19 admission (t1), 48 hours (t2), and seven days later (t3) using Olink proteomics and correlated to clinical, demographics, and therapeutic data. Older age positively correlated with decorin, pleiotrophin, and TNFRS21 but inversely correlated with chemokine (both C-C and C-X-C type) ligands, monocyte attractant proteins (MCP) and TNFRS14. The burden of pre-existing conditions was positively correlated with MCP-4, CAIX, TWEAK, TNFRS12A, and PD-L2 levels. Individuals with COVID-19 demonstrated increased expression of several chemokines, most notably from the C-C and C-X-C family, as well as MCP-1 and MCP-3 early in the course of the disease. Similarly, deceased individuals had elevated MCP-1 and MCP-3 as well as Gal-9 serum levels. LAMP3, GZMB, and LAG3 at admission correlated with mortality. Only CX3CL13 and MCP-4 correlated positively with APACHE score and length of stay, while decorin, MUC-16 and TNFRSF21 with being admitted to the ICU. We also identified several organ-failure-specific immunological markers, including those for respiratory (IL-18, IL-15, Gal-9) or kidney failure (CD28, VEGF). Treatment with hydroxychloroquine, remdesivir, convalescent plasma, and steroids had a very limited effect on the serum variation of biomarkers. Our study identified several potential targets related to COVID-19 heterogeneity (MCP-1, MCP-3, MCP-4, TNFR superfamily members, and programmed death-ligand), suggesting a potential role of these molecules in the pathology of COVID-19.

show abstract

Section: Discussionmentioning

confidence: 92%

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Also, we showed that RPTECs enhance c-Myc expression in CD4+ T-cells. Co-stimulation, and especially CD80/86 interaction with CD28, is necessary for c-Myc upregulation in T-cells, which in turn, by inducing aerobic glycolysis, favors T-cell proliferation [ 39 , 40 , 41 , 42 , 43 ]. Remarkably, a recent study showed that in human CD4+ T cells, CD28 upregulates glycolysis independently of TCR engagement by increasing c-Myc [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion

Eleftheriadis

Pissas

Crespo

et al. 2021

IJMS

View full text Add to dashboard Cite

Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated the possible role of primary human proximal renal tubular epithelial cells (RPTECs) in direct allorecognition by CD4+ T-cells and the effect of anoxia-reoxygenation. In cell culture, we detected that RPTECs express all the required molecules for CD4+ T-cell activation (HLA-DR, CD80, and ICAM-1). Anoxia-reoxygenation decreased HLA-DR and CD80 but increased ICAM-1. Following this, RPTECs were co-cultured with alloreactive CD4+ T-cells. In T-cells, zeta chain phosphorylation and c-Myc increased, indicating activation of T-cell receptor and co-stimulation signal transduction pathways, respectively. T-cell proliferation assessed with bromodeoxyuridine assay and with the marker Ki-67 increased. Previous culture of RPTECs under anoxia raised all the above parameters in T-cells. FOXP3 remained unaffected in all cases, signifying that proliferating T-cells were not differentiated towards a regulatory phenotype. Our results support that direct allorecognition may be mediated by RPTECs even in the absence of donor-derived professional APCs. Also, ischemia-reperfusion injury of the graft may enhance the above capacity of RPTECs, increasing the possibility of acute rejection.

show abstract

“…In addition, in PDA patients, CD8 + TILs were negatively correlated with LDHA and PKM2 expression [ 71 ], while T cell involvement was reported for GLUT1 [ 18 ], FOXM1 [ 65 ] and ENO1 [ 81 , 91 ]. Moreover, tumoral T cell metabolism was affected by immune checkpoint signaling; indeed, PD1 expression inhibited the glycolysis pathway shifting the metabolism towards lipolysis and fatty acid oxidation [ 208 ]. Of note, the use of the immune checkpoint blockade was able to inhibit glycolysis in tumor cells, together with the enhancement of CD8 + TIL glycolysis and effector function, such as IFN-γ production [ 205 ].…”

Section: Metabolic Reprogramming To Increase the Immune Response mentioning

confidence: 99%

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.

show abstract

CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation

Cited by 62 publications

References 50 publications

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics

A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Contact Info

Product

Resources

About