Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy
Vinhkhang N. Nguyen,
Kenneth J. Livak,
Donna S. Neuberg,
Robert J Soiffer,
Edwin P. Alyea,
Catherine J. Wu
Posted 10 Jul 2020
bioRxiv DOI: 10.1101/2020.07.08.194332
Posted 10 Jul 2020
Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of terminal (TEX) and precursor (TPEX) exhausted subsets, respectively, defined DLI response. A contrasting, heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, TPEX cells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Our unbiased dissection of the TME using a Bayesian method, Symphony, defined the T cell circuitry underlying effective human anti-leukemic immune responses that may be broadly relevant to other exhaustion antagonists across cancers. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of therapeutic scenarios beyond oncology. ### Competing Interest Statement C.J.W. is a co-founder of Neon Therapeutics and member of its scientific advisory board. P.B. reports equity in Agenus, Amgen, Breakbio Corp., Johnson & Johnson, Exelixis, and BioNTech. C.J.W. and D.N. receive research funding from Pharmacyclics. D.N. reports stock ownership in Madrigal Pharmaceuticals. V.N.N. is an employee of Bluebird Bio. J.R. receives research funding from Amgen, Equillium and Kite/Gilead and serves on Data Safety Monitoring Committees for AvroBio and Scientific Advisory Boards for Falcon Therapeutics, LifeVault Bio, Rheos Medicines, Talaris Therapeutics and TScan Therapeutics. The remaining authors declare no competing financial interests.
- Downloaded 1,495 times
- Download rankings, all-time:
- Site-wide: 10,777
- In cancer biology: 215
- Year to date:
- Site-wide: 8,441
- Since beginning of last month:
- Site-wide: 14,284
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!