Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Abstract Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44789-z |
| _version_ | 1827329068804079616 |
|---|---|
| author | Isaac Dean Colin Y. C. Lee Zewen K. Tuong Zhi Li Christopher A. Tibbitt Claire Willis Fabrina Gaspal Bethany C. Kennedy Veronika Matei-Rascu Rémi Fiancette Caroline Nordenvall Ulrik Lindforss Syed Murtuza Baker Christian Stockmann Veronika Sexl Scott A. Hammond Simon J. Dovedi Jenny Mjösberg Matthew R. Hepworth Gianluca Carlesso Menna R. Clatworthy David R. Withers |
| author_facet | Isaac Dean Colin Y. C. Lee Zewen K. Tuong Zhi Li Christopher A. Tibbitt Claire Willis Fabrina Gaspal Bethany C. Kennedy Veronika Matei-Rascu Rémi Fiancette Caroline Nordenvall Ulrik Lindforss Syed Murtuza Baker Christian Stockmann Veronika Sexl Scott A. Hammond Simon J. Dovedi Jenny Mjösberg Matthew R. Hepworth Gianluca Carlesso Menna R. Clatworthy David R. Withers |
| author_sort | Isaac Dean |
| collection | DOAJ |
| description | Abstract Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived. |
| first_indexed | 2024-03-07T15:27:32Z |
| format | Article |
| id | doaj.art-27d36aa7031e441daba36d10fc106a98 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T15:27:32Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-27d36aa7031e441daba36d10fc106a982024-03-05T16:35:49ZengNature PortfolioNature Communications2041-17232024-01-0115111810.1038/s41467-024-44789-zRapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunityIsaac Dean0Colin Y. C. Lee1Zewen K. Tuong2Zhi Li3Christopher A. Tibbitt4Claire Willis5Fabrina Gaspal6Bethany C. Kennedy7Veronika Matei-Rascu8Rémi Fiancette9Caroline Nordenvall10Ulrik Lindforss11Syed Murtuza Baker12Christian Stockmann13Veronika Sexl14Scott A. Hammond15Simon J. Dovedi16Jenny Mjösberg17Matthew R. Hepworth18Gianluca Carlesso19Menna R. Clatworthy20David R. Withers21Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamDepartment of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of CambridgeDepartment of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of CambridgeInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska InstitutetInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamDepartment of Molecular Medicine and Surgery, Karolinska Institutet and Department of Pelvic Cancer, Karolinska University HospitalDepartment of Molecular Medicine and Surgery, Karolinska Institutet and Department of Pelvic Cancer, Karolinska University HospitalDivision of Informatics, Imaging & Data Science, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester Academic Health Science CentreInstitute of Anatomy, University of ZurichInstitute of Pharmacology and Toxicology, University of Veterinary MedicineEarly Oncology R&DEarly Oncology R&DCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska InstitutetLydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester Academic Health Science CentreEarly Oncology R&DDepartment of Medicine, Molecular Immunity Unit, Medical Research Council Laboratory of Molecular Biology, University of CambridgeInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamAbstract Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.https://doi.org/10.1038/s41467-024-44789-z |
| spellingShingle | Isaac Dean Colin Y. C. Lee Zewen K. Tuong Zhi Li Christopher A. Tibbitt Claire Willis Fabrina Gaspal Bethany C. Kennedy Veronika Matei-Rascu Rémi Fiancette Caroline Nordenvall Ulrik Lindforss Syed Murtuza Baker Christian Stockmann Veronika Sexl Scott A. Hammond Simon J. Dovedi Jenny Mjösberg Matthew R. Hepworth Gianluca Carlesso Menna R. Clatworthy David R. Withers Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity Nature Communications |
| title | Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity |
| title_full | Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity |
| title_fullStr | Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity |
| title_full_unstemmed | Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity |
| title_short | Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity |
| title_sort | rapid functional impairment of natural killer cells following tumor entry limits anti tumor immunity |
| url | https://doi.org/10.1038/s41467-024-44789-z |
| work_keys_str_mv | AT isaacdean rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT colinyclee rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT zewenktuong rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT zhili rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT christopheratibbitt rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT clairewillis rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT fabrinagaspal rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT bethanyckennedy rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT veronikamateirascu rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT remifiancette rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT carolinenordenvall rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT ulriklindforss rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT syedmurtuzabaker rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT christianstockmann rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT veronikasexl rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT scottahammond rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT simonjdovedi rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT jennymjosberg rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT matthewrhepworth rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT gianlucacarlesso rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT mennarclatworthy rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity AT davidrwithers rapidfunctionalimpairmentofnaturalkillercellsfollowingtumorentrylimitsantitumorimmunity |