Ke Jin, Rebecca Fuchs, Julie Clor, Jenna L Pappalardo, Kaustubh Parashar, Soonweng Cho, Nigel P C Walker, Matthew J Walters, Ester Fernandez-Salas, Christine E Bowman
{"title":"利用细胞外ATP抑制CD39增强抗肿瘤免疫。","authors":"Ke Jin, Rebecca Fuchs, Julie Clor, Jenna L Pappalardo, Kaustubh Parashar, Soonweng Cho, Nigel P C Walker, Matthew J Walters, Ester Fernandez-Salas, Christine E Bowman","doi":"10.1093/jimmun/vkaf187","DOIUrl":null,"url":null,"abstract":"<p><p>CD39 (encoded by ENTPD1) has emerged as a target for oncologic therapies. Inhibition of CD39 preserves extracellular adenosine triphosphate (eATP) and decreases extracellular adenosine (eADO) formation, thereby increasing the eATP/eADO ratio and promoting immune stimulation. RNA expression profiling of eATPases across all solid tumors in The Cancer Genome Atlas (TCGA) demonstrates that ENTPD1 has the most widespread expression. Enzymatic characterization of these eATPases shows CD39 to have the greatest catalytic activity at pH 6.8, the prevailing mildly acidic pH of the tumor microenvironment, highlighting CD39 as an ideal therapeutic target of choice for eATP preservation. In an MC38 tumor model, inhibition of CD39 led to enhanced myeloid cell activation and tumor control when combined with anti-PD-1 therapy. To better understand how the murine results would translate to a human setting in which chemotherapy is the standard of care, a human monocyte-derived dendritic cell/T cell/carcinoma cell line coculture system was developed. CD39 inhibition led to greater production of IL-2, granzyme B, and IFNγ, demonstrating that chemotherapy-induced eATP generation is sufficient to promote myeloid cell activation, resulting in enhanced T cell function. Using the coculture system, we generated the first transcriptional eATP signature developed on primary human myeloid cells and applied it to real-world datasets, illustrating a response to eATP that can be measured in human tumors. These studies provide a mechanistic rationale for CD39 inhibition to promote antitumor immunity via the enhancement of eATP-driven myeloid cell activation of T cells across a variety of tumor settings and eATP-generative modalities.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Harnessing CD39 inhibition to boost antitumor immunity with extracellular ATP.\",\"authors\":\"Ke Jin, Rebecca Fuchs, Julie Clor, Jenna L Pappalardo, Kaustubh Parashar, Soonweng Cho, Nigel P C Walker, Matthew J Walters, Ester Fernandez-Salas, Christine E Bowman\",\"doi\":\"10.1093/jimmun/vkaf187\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CD39 (encoded by ENTPD1) has emerged as a target for oncologic therapies. Inhibition of CD39 preserves extracellular adenosine triphosphate (eATP) and decreases extracellular adenosine (eADO) formation, thereby increasing the eATP/eADO ratio and promoting immune stimulation. RNA expression profiling of eATPases across all solid tumors in The Cancer Genome Atlas (TCGA) demonstrates that ENTPD1 has the most widespread expression. Enzymatic characterization of these eATPases shows CD39 to have the greatest catalytic activity at pH 6.8, the prevailing mildly acidic pH of the tumor microenvironment, highlighting CD39 as an ideal therapeutic target of choice for eATP preservation. In an MC38 tumor model, inhibition of CD39 led to enhanced myeloid cell activation and tumor control when combined with anti-PD-1 therapy. To better understand how the murine results would translate to a human setting in which chemotherapy is the standard of care, a human monocyte-derived dendritic cell/T cell/carcinoma cell line coculture system was developed. CD39 inhibition led to greater production of IL-2, granzyme B, and IFNγ, demonstrating that chemotherapy-induced eATP generation is sufficient to promote myeloid cell activation, resulting in enhanced T cell function. Using the coculture system, we generated the first transcriptional eATP signature developed on primary human myeloid cells and applied it to real-world datasets, illustrating a response to eATP that can be measured in human tumors. These studies provide a mechanistic rationale for CD39 inhibition to promote antitumor immunity via the enhancement of eATP-driven myeloid cell activation of T cells across a variety of tumor settings and eATP-generative modalities.</p>\",\"PeriodicalId\":16045,\"journal\":{\"name\":\"Journal of immunology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jimmun/vkaf187\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jimmun/vkaf187","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Harnessing CD39 inhibition to boost antitumor immunity with extracellular ATP.
CD39 (encoded by ENTPD1) has emerged as a target for oncologic therapies. Inhibition of CD39 preserves extracellular adenosine triphosphate (eATP) and decreases extracellular adenosine (eADO) formation, thereby increasing the eATP/eADO ratio and promoting immune stimulation. RNA expression profiling of eATPases across all solid tumors in The Cancer Genome Atlas (TCGA) demonstrates that ENTPD1 has the most widespread expression. Enzymatic characterization of these eATPases shows CD39 to have the greatest catalytic activity at pH 6.8, the prevailing mildly acidic pH of the tumor microenvironment, highlighting CD39 as an ideal therapeutic target of choice for eATP preservation. In an MC38 tumor model, inhibition of CD39 led to enhanced myeloid cell activation and tumor control when combined with anti-PD-1 therapy. To better understand how the murine results would translate to a human setting in which chemotherapy is the standard of care, a human monocyte-derived dendritic cell/T cell/carcinoma cell line coculture system was developed. CD39 inhibition led to greater production of IL-2, granzyme B, and IFNγ, demonstrating that chemotherapy-induced eATP generation is sufficient to promote myeloid cell activation, resulting in enhanced T cell function. Using the coculture system, we generated the first transcriptional eATP signature developed on primary human myeloid cells and applied it to real-world datasets, illustrating a response to eATP that can be measured in human tumors. These studies provide a mechanistic rationale for CD39 inhibition to promote antitumor immunity via the enhancement of eATP-driven myeloid cell activation of T cells across a variety of tumor settings and eATP-generative modalities.
期刊介绍:
The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)