Silencing adenosine A2a receptor enhances dendritic cell-based cancer immunotherapy

Masjedi, Ali; Ahmadi, Armin; Ghani, Sepideh; Malakotikhah, Farinaz; Nabi‐Afjadi, Mohsen; Irandoust, Mahzad; Kiani, Fariba Karoon; Asl, Sima Heydarzadeh; Atyabi, Fatemeh; Hassannia, Hadi; Hojjat‐Farsangi, Mohammad; Namdar, Afshin; Ghalamfarsa, Ghasem; Jadidi‐Niaragh, Farhad

doi:10.1016/j.nano.2020.102240

Cited by 26 publications

(15 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further investigated the MDSC function in each group by staining with 2′,7′‐Dichlorofluorescein diacetate (H 2 DCF) to measure the intracellular reactive oxygen species (ROS) content. [ 9 ] There was a remarkable decrease in H 2 DCF MFI in the PPDAIn PTT group (Figure 7D), indicating that PPDAIn PTT treatment decreased the ability of MDSCs to generate ROS, thus impairing its inhibitory effect on lymphocytes. Additionally, we characterized tumor Tregs using immunohistochemistry (IHC).…”

Section: Resultsmentioning

confidence: 99%

“…[ 6 ] As hydrolyzed from adenosine triphosphate (ATP), adenosine binds the adenosine 2A receptor (A2AR) on immune cells and cancer cells to exert pleiotropic immunosuppressive effects. [ 7 ] This binding enables tumor cells to escape immune surveillance by limiting the functionality of multiple infiltrating protective immune cells, including T cells, [ 8 ] DCs, [ 9 ] and natural killer (NK) cells. [ 10 ] The adenosine‐A2AR pathway also enhances the activity of immunosuppressive cell types, such as MDSCs and regulatory T cells (Tregs), and promotes survival, proliferation, migration, and invasion of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Liu

et al. 2022

Advanced Science

View full text Add to dashboard Cite

The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine‐A2AR negative feedback pathway is highlighted during photothermal‐induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal‐induced ICD process. It is possible to achieve a robust ICD‐based immunotherapy via targeting the adenosine‐A2AR metabolic pathway. In this regard, an A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to enable tumor‐specific delivery and photothermal‐induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid‐derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Liu

et al. 2022

Advanced Science

View full text Add to dashboard Cite

show abstract

“…In our ranking provided (Figure 6), approximately 80% of the top ranked receptors had a known link to cancer. Notable entries that have reported connections to cancer include the C-C Chemokine receptor (CCR) type 5, which has been linked to regulatory T cells mediating tumor growth [61], and type 2 as a key player in microenvironment-derived tumor progression [62,63]; LPA (Lysophosphatidic acid) receptor LPAR6, upregulated in bladder cancer [64]; GRM (Metabotropic glutamate) receptors 2 (GRM2) and 8 (GRM8), respectively known for dysregulating signaling pathways that are crucial in cancer prevention and activating variants in squamous cell lung cancer [65][66][67]; serotonin receptors 5HT1A (HTR1A) and 5HT5A (HTR5A), the former known to be involved in at least breast, ovarian and pancreatic cancer, and the latter recently linked to breast cancer [39,68]; and the adenosine A1 (ADORA1) and A2A (ADORA2A) receptors, linked to the progression and metastasis of a variety of cancer types as well as immune escape and immunotherapy [69][70][71][72]. The P2Y receptor family member 10 (P2RY10) is an example of GPCR not previously linked directly to cancer, found in the first Pareto front in rank eight.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

Bongers

González

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the 'DRY' motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family.

show abstract

“…These findings prompted novel pre-clinical and clinical therapeutic approaches targeting different adenosinergic signalling components and the whole purinome. Notable targets in these efforts have included CD39 [37,38], CD73 [13,39], CD38 [40], and A 2A R [41][42][43]. Other studies have focused on chimeric antigen receptor T (CAR-T) cells with A2AR suppression to block T-cell functionality [44,45] and on combination therapies targeting the above-mentioned proteins together with anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1) [46] or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [47].…”

Section: Current Therapeutic Focusmentioning

confidence: 99%

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

Kotulová

Hajdúch

Džubák

2021

IJMS

View full text Add to dashboard Cite

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

show abstract

Silencing adenosine A2a receptor enhances dendritic cell-based cancer immunotherapy

Cited by 26 publications

References 37 publications

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

Contact Info

Product

Resources

About