Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context
Summary: Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorabl...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424000380 |
| _version_ | 1827353636060004352 |
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| author | Francesca Di Modugno Anna Di Carlo Sheila Spada Belinda Palermo Lorenzo D'Ambrosio Daniel D'Andrea Gaia Morello Beatrice Belmonte Isabella Sperduti Vittoria Balzano Enzo Gallo Roberta Melchionna Mariangela Panetta Giulia Campo Francesca De Nicola Frauke Goeman Barbara Antoniani Silvia Carpano Gianmaria Frigè Sarah Warren Filippo Gallina Diether Lambrechts Jieyi Xiong Benjamin G. Vincent Nathan Wheeler Dante S. Bortone Federico Cappuzzo Francesco Facciolo Claudio Tripodo Paolo Visca Paola Nisticò |
| author_facet | Francesca Di Modugno Anna Di Carlo Sheila Spada Belinda Palermo Lorenzo D'Ambrosio Daniel D'Andrea Gaia Morello Beatrice Belmonte Isabella Sperduti Vittoria Balzano Enzo Gallo Roberta Melchionna Mariangela Panetta Giulia Campo Francesca De Nicola Frauke Goeman Barbara Antoniani Silvia Carpano Gianmaria Frigè Sarah Warren Filippo Gallina Diether Lambrechts Jieyi Xiong Benjamin G. Vincent Nathan Wheeler Dante S. Bortone Federico Cappuzzo Francesco Facciolo Claudio Tripodo Paolo Visca Paola Nisticò |
| author_sort | Francesca Di Modugno |
| collection | DOAJ |
| description | Summary: Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. Methods: Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. Findings: Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTβR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTβR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTβR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. Interpretation: This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. Funding: This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, “Ricerca Corrente” granted by the Italian Ministry of Health. |
| first_indexed | 2024-03-08T03:30:17Z |
| format | Article |
| id | doaj.art-5fd739eb5c1748ce8a0ed4de3fe1985a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T03:30:17Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-5fd739eb5c1748ce8a0ed4de3fe1985a2024-02-11T05:11:07ZengElsevierEBioMedicine2352-39642024-03-01101105003Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in contextFrancesca Di Modugno0Anna Di Carlo1Sheila Spada2Belinda Palermo3Lorenzo D'Ambrosio4Daniel D'Andrea5Gaia Morello6Beatrice Belmonte7Isabella Sperduti8Vittoria Balzano9Enzo Gallo10Roberta Melchionna11Mariangela Panetta12Giulia Campo13Francesca De Nicola14Frauke Goeman15Barbara Antoniani16Silvia Carpano17Gianmaria Frigè18Sarah Warren19Filippo Gallina20Diether Lambrechts21Jieyi Xiong22Benjamin G. Vincent23Nathan Wheeler24Dante S. Bortone25Federico Cappuzzo26Francesco Facciolo27Claudio Tripodo28Paolo Visca29Paola Nisticò30Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy; Corresponding author.Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyDepartment of Biosciences, School of Science and Technology, Nottingham Trent University, New Hall Block - Room 171, Clifton Campus - NG11 8NS, Nottingham, United KingdomTumor Immunology Unit, Department of Health Sciences, University of Palermo, Corso Tukory 211, 90134, Palermo, ItalyTumor Immunology Unit, Department of Health Sciences, University of Palermo, Corso Tukory 211, 90134, Palermo, ItalyBiostatistics and Scientific Direction, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyPathology Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalySAFU Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalySAFU Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyPathology Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalySecond Division of Medical Oncology, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, Milan, ItalyNanoString Technologies Inc., 530 Fairview Ave N, Seattle, WA, 98109, USAThoracic-Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144 Rome, ItalyCenter for Cancer Biology, Herestraat 49 box 912, VIB, 3000, Leuven, BelgiumCenter for Cancer Biology, Herestraat 49 box 912, VIB, 3000, Leuven, BelgiumLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 5206 Marsico Hall, Chapel Hill, NC, 27599, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 5206 Marsico Hall, Chapel Hill, NC, 27599, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 5206 Marsico Hall, Chapel Hill, NC, 27599, USASecond Division of Medical Oncology, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyThoracic-Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144 Rome, ItalyTumor Immunology Unit, Department of Health Sciences, University of Palermo, Corso Tukory 211, 90134, Palermo, ItalyPathology Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, ItalyTumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Via E. Chianesi 53, 00144, Rome, Italy; Corresponding author.Summary: Background: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. Methods: Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. Findings: Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTβR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTβR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTβR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. Interpretation: This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. Funding: This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, “Ricerca Corrente” granted by the Italian Ministry of Health.http://www.sciencedirect.com/science/article/pii/S2352396424000380Tumor microenvironmentTertiary lymphoid structuresCancer-associated fibroblastsImmune checkpoint blockadeResistance to immunotherapyEpithelial mesenchymal transition |
| spellingShingle | Francesca Di Modugno Anna Di Carlo Sheila Spada Belinda Palermo Lorenzo D'Ambrosio Daniel D'Andrea Gaia Morello Beatrice Belmonte Isabella Sperduti Vittoria Balzano Enzo Gallo Roberta Melchionna Mariangela Panetta Giulia Campo Francesca De Nicola Frauke Goeman Barbara Antoniani Silvia Carpano Gianmaria Frigè Sarah Warren Filippo Gallina Diether Lambrechts Jieyi Xiong Benjamin G. Vincent Nathan Wheeler Dante S. Bortone Federico Cappuzzo Francesco Facciolo Claudio Tripodo Paolo Visca Paola Nisticò Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context EBioMedicine Tumor microenvironment Tertiary lymphoid structures Cancer-associated fibroblasts Immune checkpoint blockade Resistance to immunotherapy Epithelial mesenchymal transition |
| title | Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context |
| title_full | Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context |
| title_fullStr | Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context |
| title_full_unstemmed | Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context |
| title_short | Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerResearch in context |
| title_sort | tumoral and stromal hmena isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancerresearch in context |
| topic | Tumor microenvironment Tertiary lymphoid structures Cancer-associated fibroblasts Immune checkpoint blockade Resistance to immunotherapy Epithelial mesenchymal transition |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424000380 |
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