Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine

通过靶向 MDSC 衍生的腺苷克服癌症免疫治疗的耐药性

基本信息

批准号：
10333211
负责人：
Kavitha Yaddanapudi
金额：
$ 27.08万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333211
关键词：
5&apos -Nucleotidase Adenosine Adopted Advanced Malignant Neoplasm Attenuated CD8-Positive T-Lymphocytes CD8B1 gene CREB1 gene Cancer Center Cancer Model Cancer Patient Cattle Cell physiology Cell surface Cells Child Clinical Consumption Critical Pathways Cyclic AMP Data Dinoprostone Disease Enzymes Epidermal Growth Factor Receptor FDA approved Frequencies Generations Goals Homing Human Immune Immune Cell Suppression Immune checkpoint inhibitor Immune system Immunotherapeutic agent Immunotherapy Impairment Implant In Vitro In complete remission Inosine Knock-out Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Molecular Mus Myeloid-derived suppressor cells Non-Small-Cell Lung Carcinoma Nonmetastatic Nucleosides Outcome PD-1 inhibitors Pathway interactions Patients Polyethylene Glycols Prostaglandin Inhibition Purine Nucleosides Regulation Resistance STAT3 gene Severe Combined Immunodeficiency Signal Pathway Signal Transduction T-Cell Activation T-Lymphocyte Testing Transgenic Model Tumor Immunity Tumor-Derived adenosine deaminase anti-CTLA4 antibodies anti-PD-1 anti-PD1 antibodies anti-PD1 therapy cancer immunotherapy clinically relevant conditional knockout effector T cell enzyme replacement therapy extracellular improved in vivo inhibitor inhibitor therapy insight monocyte mouse model neoplastic cell novel objective response rate pembrolizumab programmed cell death ligand 1 response therapeutic target therapy development therapy resistant transcription factor tumor tumor growth tumor immunology tumor microenvironment

5&apos -Nucleotidase Adenosine Adopted Advanced Malignant Neoplasm Attenuated CD8-Positive T-Lymphocytes CD8B1 gene CREB1 gene Cancer Center Cancer Model Cancer Patient Cattle Cell physiology Cell surface Cells Child Clinical Consumption Critical Pathways Cyclic AMP Data Dinoprostone Disease Enzymes Epidermal Growth Factor Receptor FDA approved Frequencies Generations Goals Homing Human Immune Immune Cell Suppression Immune checkpoint inhibitor Immune system Immunotherapeutic agent Immunotherapy Impairment Implant In Vitro In complete remission Inosine Knock-out Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Molecular Mus Myeloid-derived suppressor cells Non-Small-Cell Lung Carcinoma Nonmetastatic Nucleosides Outcome PD-1 inhibitors Pathway interactions Patients Polyethylene Glycols Prostaglandin Inhibition Purine Nucleosides Regulation Resistance STAT3 gene Severe Combined Immunodeficiency Signal Pathway Signal Transduction T-Cell Activation T-Lymphocyte Testing Transgenic Model Tumor Immunity Tumor-Derived adenosine deaminase anti-CTLA4 antibodies anti-PD-1 anti-PD1 antibodies anti-PD1 therapy cancer immunotherapy clinically relevant conditional knockout effector T cell enzyme replacement therapy extracellular improved in vivo inhibitor inhibitor therapy insight monocyte mouse model neoplastic cell novel objective response rate pembrolizumab programmed cell death ligand 1 response therapeutic target therapy development therapy resistant transcription factor tumor tumor growth tumor immunology tumor microenvironment

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项目摘要

Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy using immune checkpoint inhibitors (ICIs; e.g. anti-PD-1, anti-CTLA-4 antibodies) has revolutionized the treatment of metastatic lung cancer, resulting in long-term complete responses for many patients. Nevertheless, there remains an urgent need for new strategies because not all patients respond to ICIs; moreover, resistance can occur in those that do. Myeloid-derived suppressor cells (MDSCs), in particular, monocytic MDSCs (MMDSCs) are potent immunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. Since M-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival, we postulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside, adenosine, is produced in copious amounts within the tumor microenvironment (TME), where it serves to suppress the immune system and promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediate resistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellular AMP by the cell surface enzyme, CD73 (ecto-5’-nucleotidase; AMP → adenosine). Our preliminary studies demonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity, in large part, by directly inducing cell surface CD73 expression via a novel PGE2→cAMP→CREB/STAT3 pathway leading to increased immune suppressive adenosine within the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73 expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+ T cell activation resulting, ultimately, in anti-PD-1 immunotherapeutic resistance A major goal of this proposal is to test the antitumor efficacy of a novel cancer immunotherapy involving systemic administration of adenosine deaminase (ADA)—an enzyme that irreversibly converts adenosine into inosine, a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved for use as an enzyme replacement therapy in children with ADA-associated severe combined immunodeficiency (ADA-SCID). We hypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumors to PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectives, the following aims are proposed: 1) Delineate the signaling pathway and molecular mechanisms by which PGE2 induces CD73 expression in M-MDSCs; 2) Determine whether inhibition of the PGE2→cAMP→CREB/STAT3→CD73→adenosine pathway attenuates anti-PD-1 resistance in a mouse model of lung cancer; and 3) Validate PGE2 → CD73+ M-MDSC → adenosine mediated anti-PD-1 resistance pathway in lung cancer patients receiving pembrolizumab therapy. Our proposed study will provide important insights towards developing a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

肺癌是一种普遍的疾病，每年都会消耗许多生命。使用免疫切除点抑制剂（ICI；例如抗PD-1，抗CTLA-4抗体）的癌症免疫疗法彻底改变了转移性肺癌的治疗，从而对许多患者产生了长期完全反应。然而，迫切需要新策略，因为并非所有患者都对ICIS做出反应。此外，在那些做的人中可能会发生抵抗。髓样衍生的抑制细胞（MDSC），尤其是单核细胞MDSC（MMDSC）是潜在的免疫抑制先天性免疫力，可积极抑制CD8+ T细胞肿瘤居住和激活。由于多种人类癌症中M-MDSC水平升高并与改善患者的生存相关，因此我们假设这些细胞有助于抗PD-1耐药性。嘌呤核外侧腺苷在肿瘤微环境（TME）内以大量量生产，在该环境中可抑制免疫系统并促进肿瘤生长。有证据表明，腺苷过量生产可以介导对ICIS的耐药性。通过细胞表面酶CD73（ECTO-5'-核苷酸酶； AMP→腺苷），通过细胞外放大器的酶促转化来产生免疫抑制腺苷。我们的初步研究表明，肿瘤细胞衍生的前列腺素E2（PGE2）在很大程度上通过直接诱导细胞表面CD73表达通过新型PGE2→CAMP→CREB/STAT3途径来维持M-MDSC抑制活性，从而导致TME中的免疫糖糖苷增加。该提议的总体假设是，肿瘤细胞衍生的PGE2决定了M-MDSC中的CD73表达，从而导致腺苷依赖性抑制抗肿瘤CD8+ T细胞激活的抑制作用大幅增加，最终导致抗PD-1在抗PD-1中，该建议的主要是对抗肿瘤的抗性癌症的主要范围，这是对抗肿瘤效应的主要效率。死亡酶（ADA） - 一种不可逆地将腺苷转化为一种非免疫性核外侧的酶。牛ADA（PEG-ADA）的Pegypatation版本已经被FDA批准用于患有ADA相关的严重合并免疫缺陷（ADA-SCID）儿童的酶替代疗法。我们假设通过PEG-ADA敏感性肿瘤对PD-1抑制剂治疗，腺苷介导的T细胞免疫抑制的耗竭，并改善NSCLC患者的临床结果。为了实现既定目标，提出了以下目的：1）描述PGE2影响M-MDSC中CD73表达的信号传导途径和分子机制； 2）确定抑制PGE2→CAMP→CREB/STAT3→CD73→腺苷途径是否会减弱肺癌小鼠模型中的抗PD-1耐药性；和3）验证PGE2→CD73+ M-MDSC→腺苷介导的肺癌患者接受pembrolizumab疗法的抗PD-1耐药途径。我们提出的研究将为开发安全和新颖的免疫疗法提供重要见解，以减轻肺癌患者的ICI耐药性。