PMID- 31411976 OWN - NLM STAT- MEDLINE DCOM- 20211122 LR - 20211122 IS - 2588-9311 (Electronic) IS - 2588-9311 (Linking) VI - 4 IP - 2 DP - 2021 Apr TI - Immunological Risk Stratification of Bladder Cancer Based on Peripheral Blood Natural Killer Cell Biomarkers. PG - 246-255 LID - S2588-9311(19)30058-6 [pii] LID - 10.1016/j.euo.2019.04.009 [doi] AB - BACKGROUND: Bladder cancer (BC) is highly immunogenic. Bacillus Calmette-Guerin (BCG) immunotherapy offers the best results in non-muscle-invasive BC (NMIBC). Natural killer cells (NKcs) play decisive roles in BCG-mediated immune response and in general cancer immune-surveillance. OBJECTIVE: To analyze killer-cell immunoglobulin-like receptors (KIRs), their human leukocyte antigen class-I (HLA-I) ligands, and the expression of DNAX Accessory Molecule-1 (DNAM-1/CD226) on peripheral blood (PB) NKcs, to identify useful predictive biomarkers in BC. DESIGN, SETTING, AND PARTICIPANTS: KIR/HLA-ligand genotypes were compared between 132 BC, 201 other solid cancers, 164 plasma cell disorders, and 615 healthy Caucasoid controls. CD226 expression was evaluated by flow cytometry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: KIR/HLA-I interactions and CD226 expression on NKcs (CD226(high) or CD226(low)) were compared across study groups, cancer stages, treatments, and progression-free and overall survival of patients, using chi-square, analysis of variance/post hoc, Kaplan-Meier/log-rank, and regression analyses. RESULTS AND LIMITATIONS: Three immunological risk groups were identified: low risk (KIR2DL1(-)L2(+)L3(-)/C1C1(-) and KIR2DL1(+)L2(+)L3(+)/C1C1(+)), intermediate risk (rest), and high risk (KIR2DL5(+)/HLA-C*16(+) and KIR2DL1(+)L2(+)L3(-)), which displayed different 10-yr progression-free rates (83.3%, 48.6%, and 0%, respectively; p<0.001) and survival rates (83.3%, 54.3%, and 6.2%, respectively; p<0.001) for muscle-invasive T2/T4, and 10-yr progression-free rates (100%, 81.6%, and 50%, respectively; p<0.05) for NMIBC-T1 treated with BCG. Immunological risk stratification had an independent prognostic value to just histological staging for survival (hazard ratio=2.93, p<0.00001, Harrell C-statistic=0.779). CD226 expression on PB NKcs improved immunological stratification in intermediate-risk T1-T4 BC patients, with survival rates of 94.1% and 66.7% for CD226(high) and CD226(low) (p<0.05), respectively. CONCLUSIONS: Immunological risk stratification will complement BC histopathology to improve risk stratification and guide the selection of personalized treatments. Understanding of the molecular mechanisms of NKc tumor immune surveillance will enable the development of future NKc-based therapies. PATIENT SUMMARY: This work describes a peripheral blood test that aids in our understanding of the immune defense mechanisms against bladder cancer, is useful for classifying patient risk, and will guide personalized treatments. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Guillamon, Concepcion F AU - Guillamon CF AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Gimeno, Lourdes AU - Gimeno L AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Server, Gerardo AU - Server G AD - Urology, HCUVA-IMIB, Murcia, Spain. FAU - Martinez-Sanchez, Maria V AU - Martinez-Sanchez MV AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Escudero, Jose F AU - Escudero JF AD - Urology, HCUVA-IMIB, Murcia, Spain. FAU - Lopez-Cubillana, Pedro AU - Lopez-Cubillana P AD - Urology, HCUVA-IMIB, Murcia, Spain. FAU - Cabezas-Herrera, Juan AU - Cabezas-Herrera J AD - Molecular Therapy and Biomarkers Research Group, Clinical Analysis Service, HCUVA-IMIB, Murcia, Spain. FAU - Campillo, Jose A AU - Campillo JA AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Abellan, Daniel J AU - Abellan DJ AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Martinez-Garcia, Jeronimo AU - Martinez-Garcia J AD - Urology, HCUVA-IMIB, Murcia, Spain. FAU - Martinez-Escribano, Jorge AU - Martinez-Escribano J AD - Dermatology Services, HCUVA-IMIB, Murcia, Spain. FAU - Ferri, Belen AU - Ferri B AD - Pathology Services, HCUVA-IMIB, Murcia, Spain. FAU - Lopez-Alvarez, Maria R AU - Lopez-Alvarez MR AD - Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, UK. FAU - Moreno-Alarcon, Cristobal AU - Moreno-Alarcon C AD - Urology, HCUVA-IMIB, Murcia, Spain. FAU - Moya-Quiles, Maria R AU - Moya-Quiles MR AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Muro, Manuel AU - Muro M AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. FAU - Minguela, Alfredo AU - Minguela A AD - Immunology Service, Hospital Clinico Universitario Virgen de la Arrixaca (HCUVA) Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain. Electronic address: alfredo.minguela@carm.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190514 PL - Netherlands TA - Eur Urol Oncol JT - European urology oncology JID - 101724904 RN - 0 (Biomarkers) SB - IM MH - Biomarkers MH - Humans MH - Killer Cells, Natural MH - Prognosis MH - Risk Assessment MH - *Urinary Bladder Neoplasms/diagnosis/genetics/therapy OTO - NOTNLM OT - Activating and inhibitory natural killer cell receptors OT - Bladder cancer OT - DNAX Accessory Molecule-1/CD226 OT - Human leukocyte antigen OT - Killer-cell immunoglobulin-like receptor OT - Natural killer cell EDAT- 2019/08/15 06:00 MHDA- 2021/11/23 06:00 CRDT- 2019/08/15 06:00 PHST- 2019/01/28 00:00 [received] PHST- 2019/03/13 00:00 [revised] PHST- 2019/04/17 00:00 [accepted] PHST- 2019/08/15 06:00 [pubmed] PHST- 2021/11/23 06:00 [medline] PHST- 2019/08/15 06:00 [entrez] AID - S2588-9311(19)30058-6 [pii] AID - 10.1016/j.euo.2019.04.009 [doi] PST - ppublish SO - Eur Urol Oncol. 2021 Apr;4(2):246-255. doi: 10.1016/j.euo.2019.04.009. Epub 2019 May 14.