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

• 批准号: 10066332
• 负责人: Kavitha Yaddanapudi
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-07 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066332
• 关键词: 5' -Nucleotidase; Ablation; Adenosine; Adopted; Advanced Malignant Neoplasm; Attenuated; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cancer Patient; Cattle; Cell physiology; Cell surface; Cells; Child; Clinical; Consumption; Data; Dinoprostone; Disease; Effectiveness; Enzymes; FDA approved; Frequencies; Generations; Goals; Health; Health Care Costs; Homing; Human; Immune; Immune Cell Suppression; Immune checkpoint inhibitor; Immune system; Immunotherapeutic agent; Immunotherapy; Impairment; Implant; In complete remission; Inosine; KRASG12D; Life; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Nucleosides; Outcome; PD-1 inhibitors; Pathway interactions; Patients; Pharmaceutical Preparations; Polyethylene Glycols; Production; Purine Nucleosides; Resistance; Scheme; Severe Combined Immunodeficiency; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transgenic Model; Tumor Immunity; Tumor-Derived; adenosine deaminase; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; cancer cell; cancer immunotherapy; clinically relevant; effector T cell; enzyme replacement therapy; extracellular; improved; inhibitor/antagonist; insight; monocyte; mouse model; neoplastic cell; novel; objective response rate; pembrolizumab; prevent; programmed cell death ligand 1; response; therapeutic target; therapy development; therapy resistant; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy using immune checkpoint inhibitors (ICIs; e.g. anti-PD-1antibody) 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 (M-MDSCs) 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 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 anti-tumor 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 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) Investigate intra-tumoral M-MDSC functional maintenance in the context of a PGE2 → CD73+ M-MDSC → adenosine dependent pathway; 2) Determine if loss/inhibition of extracellular adenosine-dependent pathway attenuates anti-PD-1 resistance in mouse models 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.

项目总结/摘要 肺癌是一种流行病，每年都会消耗许多生命。癌症免疫疗法， 免疫检查点抑制剂（ICI;例如抗PD-1抗体）已经彻底改变了转移性肺肿瘤的治疗， 癌症，导致许多患者长期完全缓解。然而，仍然有一个紧迫的 需要新的策略，因为并非所有患者都对ICI有反应;此外，耐药可能发生在那些 做骨髓来源的抑制细胞（MDSC），特别是单核细胞MDSC（M-MDSC）是有效的 免疫抑制性先天免疫细胞主动抑制CD 8 + T细胞肿瘤归巢和活化。以来 M-MDSC水平在多种人类癌症中升高，并与患者生存率降低相关，我们 假设这些细胞有助于抗PD-1抗性。嘌呤核苷，腺苷，是在 在肿瘤微环境（TME）中大量存在，用于抑制免疫系统 并促进肿瘤生长。有证据表明腺苷的过量产生可以介导 对ICI的抵抗力。免疫抑制性腺苷是通过细胞外腺苷的酶促转化产生的。 AMP通过细胞表面酶CD 73（外-5 β-核苷酸酶; AMP腺苷）。我们的初步研究 证明肿瘤细胞来源的前列腺素E2（PGE 2）维持M-MDSC抑制活性， 部分通过直接诱导细胞表面CD 73表达，导致免疫抑制性腺苷增加， 在TME中。该建议的总体假设是肿瘤细胞来源的PGE 2支配CD 73 在M-MDSC中的表达导致抗肿瘤CD 8+细胞的腺苷依赖性抑制显著增加 T细胞活化最终导致抗PD-1免疫耐受。该提案的一个主要目标是 是测试一种新型癌症免疫疗法的抗肿瘤功效，该疗法涉及全身施用 腺苷脱氨酶（ADA）-一种将腺苷不可逆地转化为肌苷的酶，一种非- 免疫抑制核苷。牛ADA的聚乙二醇化版本（PEG-ADA）已经被FDA批准用于 作为一种酶替代疗法，用于儿童严重联合免疫缺陷（ADA-SCID）。我们 假设PEG-ADA耗尽腺苷介导T细胞免疫抑制使肿瘤敏感 PD-1抑制剂治疗并改善NSCLC患者的临床结局。为了实现既定目标， 提出了以下目的：1）研究肿瘤内M-MDSC功能的维持， a PGE 2 → CD 73 + M-MDSC →腺苷依赖性途径; 2）确定细胞外基质的损失/抑制是否 腺苷依赖性途径减弱肺癌小鼠模型中的抗PD-1抗性;和3） 肺癌中PGE 2 → CD 73 + M-MDSC →腺苷介导的抗PD-1耐药通路 接受派姆单抗治疗的患者。我们提出的研究将提供重要的见解， 开发一种安全的新型免疫疗法，以减弱肺癌患者的ICI耐药性。

项目成果

Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment.

• DOI: 10.1158/1078-0432.ccr-21-0664
• 发表时间: 2022-05-13
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research

Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.

• DOI: 10.1126/sciadv.adg3736
• 发表时间: 2023-06-30
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Sarkar, Omar S.;Donninger, Howard;Al Rayyan, Numan;Chew, Lewis C.;Stamp, Bryce;Zhang, Xiang;Whitt, Aaron;Li, Chi;Hall, Melissa;Mitchell, Robert A.;Zippelius, Alfred;Eaton, John;Chesney, Jason A.;Yaddanapudi, Kavitha
• 通讯作者: Yaddanapudi, Kavitha