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：
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
项目类别：
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&apos -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

项目摘要

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.

项目摘要/摘要肺癌是一种普遍的疾病，每年都会消耗许多生命。癌症免疫疗法使用免疫检查点抑制剂（ICI;例如抗PD-1抗体）已彻底改变转移性肺的治疗癌症，导致许多患者的长期完全反应。然而，仍然很紧急需要新策略，因为并非所有患者都对ICIS做出反应；而且，在那些人可能会发生抵抗做。髓样衍生的抑制细胞（MDSC），特别是单核细胞MDSC（M-MDSC）是有效的免疫抑制的先天性免疫细胞积极抑制CD8+ T细胞肿瘤的归纳和激活。自从多种人类癌症中M-MDSC水平升高，并且与改善患者的生存相关，我们假设这些细胞有助于抗PD-1抗性。嘌呤核球，腺苷，在肿瘤微环境（TME）内的大量量，它用于抑制免疫系统并促进肿瘤生长。有证据表明，腺苷的生产过量会介导对ICIS的抵抗力。免疫抑制性腺苷是通过细胞外酶促转化产生的细胞表面酶的AMP CD73（Ecto-5-核苷酸酶； AMP→腺苷）。我们的初步研究证明肿瘤细胞衍生的前列腺素E2（PGE2）在很大程度上保持M-MDSC抑制活性部分，通过直接诱导细胞表面CD73表达，导致免疫抑制腺苷增加在TME中。该提议的总体假设是肿瘤细胞衍生的PGE2决定了CD73 M-MDSC中的表达导致腺苷依赖性抑制抗肿瘤CD8+的表达 T细胞激活最终在抗PD-1免疫疗法抗性中。该提议的主要目标是为了测试一种新型癌症免疫疗法的抗肿瘤效率，涉及腺苷脱氨酶（ADA） - 一种不可逆地将腺苷转化为肌苷的酶，一种非 - 免疫供应核苷。牛ADA（PEG-ADA）的PEGYPER版本已经被FDA批准了严重合并免疫缺陷（ADA-SCID）的儿童用作酶替代疗法。我们假设腺苷介导的T细胞免疫抑制的耗竭为了PD-1抑制剂疗法并改善了NSCLC患者的临床结果。为了实现既定目标，提出了以下目的：1）研究在肿瘤内M-MDSC功能维护 PGE2→CD73+ M-MDSC→依赖腺苷的途径； 2）确定损失/抑制细胞外腺苷依赖性途径在肺癌小鼠模型中抑制了抗PD-1抗性。 3）验证PGE2→CD73+ M-MDSC→腺苷介导的肺癌中抗PD-1抗性途径接受pembrolizumab治疗的患者。我们提出的研究将为您提供重要的见解开发一种安全和新颖的免疫疗法，以减轻肺癌患者的ICI耐药性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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