B Soldevilla1, C Carretero-Puche1, G Gomez-Lopez2, F Al-Shahrour2, M C Riesco3, B Gil-Calderon1, L Alvarez-Vallina4, P Espinosa-Olarte3, G Gomez-Esteves1, B Rubio-Cuesta1, J Sarmentero1, A La Salvia3, R Garcia-Carbonero5. 1. Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 28041, Madrid, Spain; Centro Nacional de Investigación Oncológica (CNIO), 28029, Madrid, Spain. 2. Bioinformatics Unit, Centro Nacional de Investigación Oncológica (CNIO), 28029, Madrid, Spain. 3. Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 28041, Madrid, Spain; Oncology Department, Hospital Universitario Doce de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain. 4. Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (i+12), 28041, Madrid, Spain; Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000, C Aarhus, Denmark. 5. Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 28041, Madrid, Spain; Oncology Department, Hospital Universitario Doce de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain; Complutense University of Madrid, Madrid, Spain. Electronic address: rgcarbonero@gmail.com.
Abstract
BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.
BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRCpatients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRCpatients.
Authors: Yulia I Nussbaum; Yariswamy Manjunath; Kanve N Suvilesh; Wesley C Warren; Chi-Ren Shyu; Jussuf T Kaifi; Matthew A Ciorba; Jonathan B Mitchem Journal: Int J Mol Sci Date: 2021-04-30 Impact factor: 5.923