TIM-3 + CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies

Author:

Minnie Simone A.1ORCID,Waltner Olivia G.1ORCID,Zhang Ping1ORCID,Takahashi Shuichiro1ORCID,Nemychenkov Nicole S.1,Ensbey Kathleen S.1,Schmidt Christine R.1ORCID,Legg Samuel R. W.1,Comstock Melissa1ORCID,Boiko Julie R.12ORCID,Nelson Ethan1,Bhise Shruti S.1,Wilkens Alec B.1ORCID,Koyama Motoko1ORCID,Dhodapkar Madhav V.34ORCID,Chesi Marta5ORCID,Riddell Stanley R.16ORCID,Green Damian J.16ORCID,Spencer Andrew789ORCID,Furlan Scott N.12ORCID,Hill Geoffrey R.16ORCID

Affiliation:

1. Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

2. Department of Pediatrics, University of Washington, Seattle, WA, USA.

3. Department of Hematology/Medical Oncology, Emory University, Atlanta, GA, USA.

4. Winship Cancer Institute, Emory University, Atlanta, GA, USA.

5. Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.

6. Division of Medical Oncology, University of Washington, Seattle, WA, USA.

7. Australian Center for Blood Diseases, Monash University/Alfred Hospital, Melbourne, VIC, Australia.

8. Department of Clinical Haematology, Monash University, Melbourne, VIC, Australia.

9. Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, VIC, Australia.

Abstract

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T PHEX ), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ + T PHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ + T PHEX . We also observed IFN-γ + T PHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19 + leukemia cells. An IFN-γ + T PHEX gene signature was recapitulated in T EX cells from human cancers, including myeloma and lymphoma. Here, we characterize a T EX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T EX found in chronic viral infections. Thus, IFN-γ + T PHEX represent a potential target for immunotherapy of blood cancers.

Publisher

American Association for the Advancement of Science (AAAS)

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3