Thread by @IamLinghua

1/15 🧵 I'm thrilled to share the fantastic news that our Pan-Cancer T cell Atlas is now live @NatureMedicine nature.com/articles/s4159… @MDAndersonNews #SingleCell #SpatialOmics #TumorMicroenvironment #CancerImmunotherapy

2/15 🧵Our team has created a pan-cancer single-cell T cell atlas that integrates 27 scRNA sequencing datasets, including 9 unique datasets from @MDAndersonNews, covering 16 cancer types. It presents the most detailed picture to date of the heterogeneity of T cells within the TME

3/15 🧵We defined 32 T cell states in this study, and further identified 7 subpopulations within the CD4+ Treg subset, 5 within the CD4+ Tfh population, and 8 states among proliferating T cells.

4/15 🧵 One of the most intriguing findings? The discovery of the stress response state (Tstr). Tstr cells are characterized by high heat shock gene expression. The presence of Tstr cells within the TME of various cancer types was validated by multiple spatial profiling methods.

5/15 🧵 What makes Tstr cells so interesting? First, while both Tstr and Tex cells may be dysfunctional within the TME, Tstr cells appear to follow a unique differentiation path, distinct from the trajectory of Tex cells, suggesting a possible new route to T-cell dysfunction

6/15 🧵 Second, this overlooked group of cells may play a role in #ImmunotherapyResistance. We consistently observed significant upregulation of heat shock gene expression in both CD4 and CD8 T cells following ICB therapy across patient cohorts, particularly in non-responders.

7/15 🧵Third, the discovery of highly abundant Tstr cells within lymphoid aggregates or even TLSs in tumor beds or surrounding tumor edges may have translational potential, given that TLSs serve as immunological hubs orchestrating anti-tumor immunity and immunotherapy response.

8/15 🧵 There are still many questions left to answer. We are not sure what triggers the Tstr state, nor do we know from which T cell subset(s) they originate, or how they communicate with and influence other cells within the tumor immune microenvironment.

9/15 🧵 Investigating the mechanistic causes of stress response in T cells and tracking their state transition along the immunotherapy course is crucial. It would be of interest to study the stress response in T cells in the context of CAR-T and other T-cell-targeting therapies.

10/15 🧵 Our T cell atlas can be accessed via singlecell.mdanderson.org/TCM/. This is a user-friendly, interactive web portal developed by @dustin13316197. This portal allows both internal and external users to visualize and query the atlas without the need for bioinformatics skills.

11/15 🧵 This work was led by @dustin13316197 a brilliant postdoctoral fellow in my lab. He also created TCellMap, github.com/Coolgenome/TCM an R script that enables to automatically align/annotate T cells from a query scRNA-seq dataset with the T cell maps generated by our study.

12/15 🧵 My heartfelt thanks to our amazing team and wonderful collaborators. We have had the immense fortune to collaborate with each of you, all of whom have generously shared your resources and expertise. This work would not have been possible without each and every one of you

13/15 🧵 @tcellsrus @humam_kadara @kevlitchfield @GreenLymphoLab @ALazarMDPhD @HusseinAbbasLab @CharlesSwanton @JafferAjaniMD @AmirJazaeri @Aiims1742 @andyfutreal @drcurran @DrMingyaoLi @DrJianHu @YYElamin @AReubenPhD @LeXiuning @Shaojunzhang19, and many others

14/15 🧵 and many others including @shumei_song @liuyunho @DapengHao @Squirrel_PhD @JiangjiangQin @ewrea. A huge shout out to the great support from @MDAndersonNews @NIHFunding @NCIsysbio @CPRITTexas @DeptofDefense, who made this research possible. Thank you!

15/15 🧵 Last but not least, we greatly appreciate the invaluable insights and constructive comments from our reviewers ❤️, Senior Editor @AnnaRanzoni ❤️, and the editorial team @NatureMedicine ❤️. Your expert critique was instrumental in refining our work 👍👍👍