Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors
BackgroundNatural killer (NK) cells are innate lymphocytes endowed with potent cytotoxic activity. The presence of tumor-associated NK cells has been correlated with better prognosis in several solid tumors including colorectal cancer (CRC). This malignant disease is the second cause of cancer death...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1578444/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850219229448503296 |
|---|---|
| author | Valentina Obino Chiara Giordano Simona Carlomagno Chiara Setti Marco Greppi Matteo Bozzo Silvia Pesce Silvia Pesce Elisa Ferretti Elisa Ferretti Simona Candiani Simona Candiani Letizia Muccio Enrico Ciferri Tania Buttiron Webber Agnese Solari Fulvia Ortolani Laura Paleari Matteo Clavarezza Andrea Barberis Marco Filauro Nicoletta Provinciali Nicoletta Provinciali Mariangela Rutigliani Emanuela Marcenaro Emanuela Marcenaro Andrea DeCensi Andrea DeCensi Mariella Della Chiesa Mariella Della Chiesa Simona Sivori Simona Sivori |
| author_facet | Valentina Obino Chiara Giordano Simona Carlomagno Chiara Setti Marco Greppi Matteo Bozzo Silvia Pesce Silvia Pesce Elisa Ferretti Elisa Ferretti Simona Candiani Simona Candiani Letizia Muccio Enrico Ciferri Tania Buttiron Webber Agnese Solari Fulvia Ortolani Laura Paleari Matteo Clavarezza Andrea Barberis Marco Filauro Nicoletta Provinciali Nicoletta Provinciali Mariangela Rutigliani Emanuela Marcenaro Emanuela Marcenaro Andrea DeCensi Andrea DeCensi Mariella Della Chiesa Mariella Della Chiesa Simona Sivori Simona Sivori |
| author_sort | Valentina Obino |
| collection | DOAJ |
| description | BackgroundNatural killer (NK) cells are innate lymphocytes endowed with potent cytotoxic activity. The presence of tumor-associated NK cells has been correlated with better prognosis in several solid tumors including colorectal cancer (CRC). This malignant disease is the second cause of cancer death worldwide and is in urgent need for novel approaches to improve current immunotherapies. Since CRC microenvironment can induce NK cell dysfunction and hinder cancer control, understanding tumor-associated NK cell features is mandatory to fully unlock their immunotherapeutic potential.PurposeOur study aims at elucidating the molecular and functional characteristics of tumor-associated NK cells in CRC focusing on the expression of immune checkpoints that critically regulate NK cell function. We performed an in-depth cytofluorimetric analysis of tumor-associated NK cells obtained by tissue dissociation of samples derived from 80 CRC patients comparing tumor with matched tumor-free tissue and peripheral blood, stratifying patients by tumor stage or MSI/MSS condition. Tumor tissue was also analyzed by immunohistochemistry.ResultsNK cells expressing immune checkpoints (i.e., KIR, NKG2A and TIM-3) were significantly enriched in tumor compared to tumor-free tissue, and an increase in PD-1+ NK cells was observed in tumors compared to peripheral blood and tumor-free tissue, indicating TME-induced modulation. Notably, tumor-associated PD-1+ NK cells characterized MSI rather than MSS CRC. In addition, tumor-associated NK cells also expressed tissue residency markers (CD103 and/or CD49a) and displayed a distinct profile also including the PD-1+ NK cell subset in MSI CRC, possibly representing NK cells recruited from circulation, retained in tumors, and reconfigured by TME signals. Importantly, tissue resident NK cells adequately expressed activating NK receptors and cytotoxic molecules.ConclusionsThese results suggest, together with an increased PD-L1 expression on MSI tumor cells, that the efficacy of immunotherapies in MSI CRC based on PD-1/PD-L1 blockade could also rely on a superior anti-tumor potential of PD-1+ NK cells. Conversely, MSS CRC, in which tumor-associated PD-1+ NK cells are scarce, could benefit more from immunotherapies blocking NKG2A and/or KIRs. Thus, novel approaches based on NK cell features related to CRC type, fully exploiting circulating and resident NK cell anti-tumor activity, could be key to next-generation therapies. |
| format | Article |
| id | doaj-art-222c4d911c6146ceb407a7aace0f614f |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-222c4d911c6146ceb407a7aace0f614f2025-08-20T02:07:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15784441578444Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumorsValentina Obino0Chiara Giordano1Simona Carlomagno2Chiara Setti3Marco Greppi4Matteo Bozzo5Silvia Pesce6Silvia Pesce7Elisa Ferretti8Elisa Ferretti9Simona Candiani10Simona Candiani11Letizia Muccio12Enrico Ciferri13Tania Buttiron Webber14Agnese Solari15Fulvia Ortolani16Laura Paleari17Matteo Clavarezza18Andrea Barberis19Marco Filauro20Nicoletta Provinciali21Nicoletta Provinciali22Mariangela Rutigliani23Emanuela Marcenaro24Emanuela Marcenaro25Andrea DeCensi26Andrea DeCensi27Mariella Della Chiesa28Mariella Della Chiesa29Simona Sivori30Simona Sivori31Department of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Medicine (DMED), University of Udine, Udine, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDirezione Scientifica, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyU.O. Medicina di Laboratorio, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyDepartment of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, Genoa, ItalyDirezione Scientifica, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Abdominal Surgery – General and Hepatobiliopancreatic Surgery Unit, E.O. Ospedali Galliera, Genoa, ItalyDivision of Medical Oncology, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDepartment of Medicine (DMED), University of Udine, Udine, ItalyALiSa, Liguria Health Authority, Genoa, ItalyDivision of Medical Oncology, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Abdominal Surgery – General and Hepatobiliopancreatic Surgery Unit, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Abdominal Surgery – General and Hepatobiliopancreatic Surgery Unit, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDivision of Medical Oncology, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Laboratory and Service – Histological and Anatomical Pathology Unit, E.O. Ospedali Galliera, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDirezione Scientifica, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyDivision of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy0Wolfson Institute of Population Health, Queen Mary University of London, London, United KingdomDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDirezione Scientifica, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyDepartment of Experimental Medicine (DIMES), University of Genoa, Genoa, ItalyDirezione Scientifica, IRCCS Ospedale Policlinico San Martino, Genoa, ItalyBackgroundNatural killer (NK) cells are innate lymphocytes endowed with potent cytotoxic activity. The presence of tumor-associated NK cells has been correlated with better prognosis in several solid tumors including colorectal cancer (CRC). This malignant disease is the second cause of cancer death worldwide and is in urgent need for novel approaches to improve current immunotherapies. Since CRC microenvironment can induce NK cell dysfunction and hinder cancer control, understanding tumor-associated NK cell features is mandatory to fully unlock their immunotherapeutic potential.PurposeOur study aims at elucidating the molecular and functional characteristics of tumor-associated NK cells in CRC focusing on the expression of immune checkpoints that critically regulate NK cell function. We performed an in-depth cytofluorimetric analysis of tumor-associated NK cells obtained by tissue dissociation of samples derived from 80 CRC patients comparing tumor with matched tumor-free tissue and peripheral blood, stratifying patients by tumor stage or MSI/MSS condition. Tumor tissue was also analyzed by immunohistochemistry.ResultsNK cells expressing immune checkpoints (i.e., KIR, NKG2A and TIM-3) were significantly enriched in tumor compared to tumor-free tissue, and an increase in PD-1+ NK cells was observed in tumors compared to peripheral blood and tumor-free tissue, indicating TME-induced modulation. Notably, tumor-associated PD-1+ NK cells characterized MSI rather than MSS CRC. In addition, tumor-associated NK cells also expressed tissue residency markers (CD103 and/or CD49a) and displayed a distinct profile also including the PD-1+ NK cell subset in MSI CRC, possibly representing NK cells recruited from circulation, retained in tumors, and reconfigured by TME signals. Importantly, tissue resident NK cells adequately expressed activating NK receptors and cytotoxic molecules.ConclusionsThese results suggest, together with an increased PD-L1 expression on MSI tumor cells, that the efficacy of immunotherapies in MSI CRC based on PD-1/PD-L1 blockade could also rely on a superior anti-tumor potential of PD-1+ NK cells. Conversely, MSS CRC, in which tumor-associated PD-1+ NK cells are scarce, could benefit more from immunotherapies blocking NKG2A and/or KIRs. Thus, novel approaches based on NK cell features related to CRC type, fully exploiting circulating and resident NK cell anti-tumor activity, could be key to next-generation therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1578444/fullhuman NK cellscolorectal cancerimmune checkpointstissue-residency markersmicrosatellite status |
| spellingShingle | Valentina Obino Chiara Giordano Simona Carlomagno Chiara Setti Marco Greppi Matteo Bozzo Silvia Pesce Silvia Pesce Elisa Ferretti Elisa Ferretti Simona Candiani Simona Candiani Letizia Muccio Enrico Ciferri Tania Buttiron Webber Agnese Solari Fulvia Ortolani Laura Paleari Matteo Clavarezza Andrea Barberis Marco Filauro Nicoletta Provinciali Nicoletta Provinciali Mariangela Rutigliani Emanuela Marcenaro Emanuela Marcenaro Andrea DeCensi Andrea DeCensi Mariella Della Chiesa Mariella Della Chiesa Simona Sivori Simona Sivori Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors Frontiers in Immunology human NK cells colorectal cancer immune checkpoints tissue-residency markers microsatellite status |
| title | Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors |
| title_full | Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors |
| title_fullStr | Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors |
| title_full_unstemmed | Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors |
| title_short | Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1+ NK cells in microsatellite instability tumors |
| title_sort | colorectal cancer infiltrating nk cell landscape analysis unravels tissue resident pd 1 nk cells in microsatellite instability tumors |
| topic | human NK cells colorectal cancer immune checkpoints tissue-residency markers microsatellite status |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1578444/full |
| work_keys_str_mv | AT valentinaobino colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT chiaragiordano colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT simonacarlomagno colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT chiarasetti colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT marcogreppi colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT matteobozzo colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT silviapesce colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT silviapesce colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT elisaferretti colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT elisaferretti colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT simonacandiani colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT simonacandiani colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT letiziamuccio colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT enricociferri colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT taniabuttironwebber colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT agnesesolari colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT fulviaortolani colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT laurapaleari colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT matteoclavarezza colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT andreabarberis colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT marcofilauro colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT nicolettaprovinciali colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT nicolettaprovinciali colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT mariangelarutigliani colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT emanuelamarcenaro colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT emanuelamarcenaro colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT andreadecensi colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT andreadecensi colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT marielladellachiesa colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT marielladellachiesa colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT simonasivori colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors AT simonasivori colorectalcancerinfiltratingnkcelllandscapeanalysisunravelstissueresidentpd1nkcellsinmicrosatelliteinstabilitytumors |