000118040 001__ 118040
000118040 005__ 20240319081010.0
000118040 0247_ $$2doi$$a10.3389/fimmu.2022.890836
000118040 0248_ $$2sideral$$a129522
000118040 037__ $$aART-2022-129522
000118040 041__ $$aeng
000118040 100__ $$aLanuza, P. M.
000118040 245__ $$aAdoptive NK Cell Transfer as a Treatment in Colorectal Cancer Patients: Analyses of Tumour Cell Determinants Correlating With Efficacy In Vitro and In Vivo
000118040 260__ $$c2022
000118040 5060_ $$aAccess copy available to the general public$$fUnrestricted
000118040 5203_ $$aBackground: 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. 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.
000118040 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/B29-17R$$9info:eu-repo/grantAgreement/EC/H2020/635342/EU/ Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer/MoTriColor$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 635342-MoTriColor$$9info:eu-repo/grantAgreement/ES/ISCIII-FEDER/PI20-00767$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R
000118040 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000118040 590__ $$a7.3$$b2022
000118040 592__ $$a2.022$$b2022
000118040 591__ $$aIMMUNOLOGY$$b35 / 161 = 0.217$$c2022$$dQ1$$eT1
000118040 593__ $$aImmunology and Allergy$$c2022$$dQ1
000118040 593__ $$aImmunology$$c2022$$dQ1
000118040 594__ $$a9.4$$b2022
000118040 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000118040 700__ $$aAlonso, M. H.
000118040 700__ $$aHidalgo, S.
000118040 700__ $$aUranga-Murillo, I.
000118040 700__ $$aGarcía-Mulero, S.
000118040 700__ $$aArnau, R.
000118040 700__ $$aSantos, C.
000118040 700__ $$aSanjuan, X.
000118040 700__ $$aSantiago, L.
000118040 700__ $$aComas, L.
000118040 700__ $$aRedrado, S.
000118040 700__ $$aPazo-Cid, R.
000118040 700__ $$aAgustin-Ferrández, M. J.
000118040 700__ $$aJaime-Sánchez, P.
000118040 700__ $$aPesini, C.
000118040 700__ $$aGálvez, E. M.
000118040 700__ $$aRamírez-Labrada, A.
000118040 700__ $$aArias, M.
000118040 700__ $$aSanz-Pamplona, R.
000118040 700__ $$0(orcid)0000-0003-0154-0730$$aPardo Jimeno, J.$$uUniversidad de Zaragoza
000118040 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000118040 773__ $$g13 (2022), 890836 [15 pp]$$pFront. immunol.$$tFrontiers in Immunology$$x1664-3224
000118040 8564_ $$s4371020$$uhttps://zaguan.unizar.es/record/118040/files/texto_completo.pdf$$yVersión publicada
000118040 8564_ $$s2568689$$uhttps://zaguan.unizar.es/record/118040/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000118040 909CO $$ooai:zaguan.unizar.es:118040$$particulos$$pdriver
000118040 951__ $$a2024-03-18-15:05:02
000118040 980__ $$aARTICLE