Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Venkatraman, Simran; Meller, Jarek; Hongeng, Suradej; Tohtong, Rutaiwan

doi:10.3390/vaccines8040735

Cited by 24 publications

(19 citation statements)

References 116 publications

(134 reference statements)

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“…As a core component of the immune response, T cells are present in the tumor microenvironment and determine the efficacy of anti-tumor immunotherapy (2). Immune checkpoints are signaling molecules on the surface of T cells that regulate their activity and participate in the immune response (3)(4)(5). It has been proved that tumor cells can escape from the immune surveillance by activating immune checkpoints which then release inhibitory signals (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

et al. 2021

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T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear. We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis in this cohort. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth. These results suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

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Section: Introductionmentioning

confidence: 99%

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

et al. 2021

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“…In particular, given multiple its molecular abnormalities, CLL is considered a highly heterogeneous disease, including patients not requiring any therapy and patients having an aggressive course with poor response to therapy [ 5 ]. Major mutations in CLL affect many cellular components including inflammatory receptors (e.g., MYD88), kinases such as MAPK (e.g., BRAF), NF-kB-related molecules (e.g., BIRC3), transcription (e.g., EGR2 and NOTCH1) and splicing factors (e.g., SF3B1), DNA damage and cell cycle control factors (e.g., ATM and TP53) [ 6 ]. These genetic abnormalities have supported the generation of novel agents against CLL which have been translated into the clinical practice towards a more targeted treatment strategy for patients [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Gonder

Largeot

Gargiulo

et al. 2021

Cancers

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Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1α are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1α being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL.

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“…4B) (Vettore, Westbrook & Tennant, 2019). Also, the negative regulation of transcription regulation from RNA polymerase II (GO:0000122) may be important in manipulating tumor microenvironment and communications of cancer cells (Venkatraman et al, 2020). In utero embryonic development process (GO:0001701) plays role in breast cancer metastasis and mammary development in utero (Howard & Veltmaat, 2013).…”

Section: Compiling Realistic Network and Identifying Nodes Causing Wimentioning

confidence: 99%

Network based multifactorial modelling of miRNA-target interactions

Yuka¹,

Yılmaz²

2021

PeerJ

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Competing endogenous RNA (ceRNA) regulations and crosstalk between various types of non-coding RNA in humans is an important and under-explored subject. Several studies have pointed out that an alteration in miRNA:target interaction can result in unexpected changes due to indirect and complex interactions. In this article, we defined a new network-based model that incorporates miRNA:ceRNA interactions with expression values. Our approach calculates network-wide effects of perturbations in the expression level of one or more nodes in the presence or absence of miRNA interaction factors such as seed type, binding energy. We carried out the analysis of large-scale miRNA:target networks from breast cancer patients. Highly perturbing genes identified by our approach coincide with breast cancer-associated genes and miRNAs. Our network-based approach takes the sponge effect into account and helps to unveil the crosstalk between nodes in miRNA:target network. The model has potential to reveal unforeseen regulations that are only evident in the network context. Our tool is scalable and can be plugged in with emerging miRNA effectors such as circRNAs, lncRNAs, and available as R package ceRNAnetsim: https://www.bioconductor.org/packages/release/bioc/html/ceRNAnetsim.html.

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Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Cited by 24 publications

References 116 publications

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Network based multifactorial modelling of miRNA-target interactions

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