CD39/CD73/A2AR pathway and cancer immunotherapy

Xia, Chenglai; Yin, Shuanghong; To, Kenneth Kin Wah; Fu, Liwu

doi:10.1186/s12943-023-01733-x

Cited by 87 publications

(55 citation statements)

References 142 publications

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“…In various cancer cell model, preclinical and clinical trials of small molecule inhibitors of ectonucleotidase resulting in decreased adenosine levels in TME. As in observed results, the immunosuppressive M2 macrophages had an enhanced expression of CD73 and CD39 in comparison with M1 macrophages [73].…”

Section: Discussionsupporting

confidence: 87%

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

DALAI,

Shah,

Soni

et al. 2024

Preprint

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Purpose Studies have reported that cellular metabolism at tumor-immune microenvironment (TiME) serve as a critical checkpoint and perturbs/supports anti-cancer immunity. Extracellular ATP (eATP) may mediate anti-cancer immune response however; its catabolism by ectonucleotidase generates immunosuppressive adenosine. Antagonist of ectonucleotidases: CD39 and CD73 have been explored as potential therapeutic. In the presented work we have tried to repurpose doxycycline for mitigating ATP metabolism with or without antagonist of ectonucleotidase. Methods eATP and adenosine level were quantified. The bone marrow-derived M1 and M2 polarized macrophages were maintained in tumor mimicking condition (TMC). Total or CD4+ Tcells were co-cultured with macrophages to understand the impact of doxycycline and antagonist of ectonucleotidase T cell/subset differentiation. Preclinical efficacy of doxycycline and ectonucleotidase antagonist and their synergy was scored in 4T1 breast carcinoma. Results Doxycycline manipulates macrophage polarization by decreasing the frequency CD206+M2 macrophages that promoted CD4+ directed CD8+ T cell mediated tumor cell lysis. Doxycycline alleviated the expression of CD39 and CD73, rescuing ATP catabolism. Doxycycline delayed tumor growth by enhancing F4/80+ CD86+ M1 macrophages and subsequently anti-tumor Tbet+ CD4+ T-cells, attenuating the frequency of FOXP3+ regulatory T cells which was cooperatively supported by ARL67156 and AMPCP (CD39 and CD73 antagonist). Doxycycline promoted CD8+T cell mediated cytotoxicity which was synergistically enhanced with ARL67156 and AMPCP ensuring a possibility of using doxycycline alone or in combination with antagonist of ectonucleotidase. Conclusion Presented data indicate a prospective usage of doxycycline as novel immune checkpoint blocker (ICB) against ectonucleotidase and may be modified/delivered appropriately as a sole ICB.

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Section: Discussionsupporting

confidence: 87%

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

DALAI,

Shah,

Soni

et al. 2024

Preprint

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“…Extracellular ATP serves as a danger signal indicative of tissue damage, and induces proinflammatory signals, such as the inflammasome 19 . CD39, together with CD73 (both found to be elevated on T cells residing in the aged spleen) mediate the breakdown of ATP to adenosine which inhibits T cell proliferation 21 .Similarly, this pathway plays a central role in mediating immunosuppression within the tumour microenvironment 60 .…”

Section: Discussionmentioning

confidence: 99%

Haem toxicity in the aged spleen impairs T-cell immunity through iron deprivation

Ezuz,

Ombashe,

watted

et al. 2024

Preprint

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Ageing profoundly impacts T cell immunity, compromising vaccine responses, susceptibility to infections, and immunosurveillance. Mechanisms of T cell ageing involve cell-intrinsic alterations and interactions with other immune and stromal cells. This study investigates how a tissue's microenvironment influences T cell ageing trajectories, following our discovery of varying rates of T cell ageing within a single host. Spleen-derived lymphocytes exhibited functional decline compared to those from lymph nodes, with proteomic analysis revealing increased expression of haem detoxification and iron storage proteins in aged spleen-derived lymphocytes. Exposure to the aged spleen microenvironment or to haem induced multiple ageing phenotypes in young lymphocytes, characterized by reduced proliferation and upregulation of the ectonucleotidases CD39 and CD73. Mechanistically, we show that T cells survive the hostile microenvironment of the aged spleen by maintaining low labile iron pools to resist ferroptosis. Finally, vaccination responses in aged mice were enhanced by timed iron infusions. Our findings underscore a trade-off between T cell survival and function in the aged host. Recent studies show how Dysfunctional T cells induce premature ageing phenotypes in multiple solid organs of a young host. Our findings highlight the bidirectional relationship between T cells and their ageing microenvironment. Understanding these mechanisms will inform strategies to enhance immune responses in the elderly.

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“…For instance, we identified abundant CD39 expression on vessels and stromal cells, in the vicinity of immune cells in both T cell high and T cell low chordomas, suggesting that the adenosine pathway might be a potential mediator of immune suppression in chordomas. Although the immunosuppressive functionalities of this pathway have mainly been described in carcinomas 34,35 , expression of CD39 was recently found to associate with increased inflammation in primary tumours as well as with increased T cell densities and PD-1 expression in recurrent undifferentiated soft tissue sarcomas 36 . Further research should determine the extent to which the adenosine pathway can modulate immune responses in this disease.…”

Section: Discussionmentioning

confidence: 99%

Multimodal profiling of chordoma immunity reveals distinct immune contextures

van Oost,

Meijer,

IJsselsteijn

et al. 2023

Preprint

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Chordomas are cancers from the axial skeleton presenting immunological hallmarks of unknown significance. In recent years, some clinical trials demonstrated that chordomas can respond to immunotherapy. We present a comprehensive characterisation of immunological features of 76 chordomas through application of a multimodal approach comprising transcriptional profiling, multidimensional immunophenotyping and TCR profiling. Chordomas generally presented an immune 'hot' microenvironment in comparison to other sarcomas, as indicated by the immunologic constant of rejection transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration. The highly infiltrated group was further characterised by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumours, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the T cell receptor repertoire compared to those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. Our findings shed light on the natural immunity against chordomas. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for chordoma patients.

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CD39/CD73/A2AR pathway and cancer immunotherapy

Cited by 87 publications

References 142 publications

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

Haem toxicity in the aged spleen impairs T-cell immunity through iron deprivation

Multimodal profiling of chordoma immunity reveals distinct immune contextures

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