Adoptive NK Cell Transfer as a Treatment in Colorectal Cancer Patients: Analyses of Tumour Cell Determinants Correlating With Efficacy In Vitro and In Vivo .

Autor:	Lanuza PM; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain., Alonso MH; Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain., Hidalgo S; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.; Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain., Uranga-Murillo I; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.; Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain.; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain., García-Mulero S; Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain.; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Arnau R; Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain., Santos C; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain., Sanjuan X; Department of Pathology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Santiago L; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.; Oncology and Pharmacology Units, HUMSICB-CSIC, Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain., Comas L; Oncology and Pharmacology Units, HUMSICB-CSIC, Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain., Redrado S; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.; Oncology and Pharmacology Units, HUMSICB-CSIC, Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain., Pazo-Cid R; Hospital Universitario Miguel Servet, Zaragoza, Spain., Agustin-Ferrández MJ; Hospital Universitario Miguel Servet, Zaragoza, Spain., Jaime-Sánchez P; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain., Pesini C; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain., Gálvez EM; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.; Oncology and Pharmacology Units, HUMSICB-CSIC, Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain., Ramírez-Labrada A; Unidad de Nanotoxicología e Inmunotoxicología (UNATI), Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain., Arias M; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.; Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain.; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain., Sanz-Pamplona R; Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain.; ARAID Foundation, Aragon Health Research Institute (IIS Aragón), Zaragoza, Spain., Pardo J; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.; Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain.; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.; ARAID Foundation, Aragon Health Research Institute (IIS Aragón), Zaragoza, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jun 07; Vol. 13, pp. 890836. Date of Electronic Publication: 2022 Jun 07 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.890836
Abstrakt:	Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC. Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity. Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA + and HLA - CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control. Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy. Competing Interests: JP reported research funding from BMS and Gilead and speaker honoraria from Gilead and Pfizer. EG reported research funding from BMS and Gilead.The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Lanuza, Alonso, Hidalgo, Uranga-Murillo, García-Mulero, Arnau, Santos, Sanjuan, Santiago, Comas, Redrado, Pazo-Cid, Agustin-Ferrández, Jaime-Sánchez, Pesini, Gálvez, Ramírez-Labrada, Arias, Sanz-Pamplona and Pardo.)
Databáze:	MEDLINE
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