Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.
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Authors
Nava Rodrigues, D
Rescigno, P
Liu, D
Yuan, W
Carreira, S
Lambros, MB
Seed, G
Mateo, J
Riisnaes, R
Mullane, S
Margolis, C
Miao, D
Miranda, S
Dolling, D
Clarke, M
Bertan, C
Crespo, M
Boysen, G
Ferreira, A
Sharp, A
Figueiredo, I
Keliher, D
Aldubayan, S
Burke, KP
Sumanasuriya, S
Fontes, MS
Bianchini, D
Zafeiriou, Z
Teixeira Mendes, LS
Mouw, K
Schweizer, MT
Pritchard, CC
Salipante, S
Taplin, M-E
Beltran, H
Rubin, MA
Cieslik, M
Robinson, D
Heath, E
Schultz, N
Armenia, J
Abida, W
Scher, H
Lord, C
D'Andrea, A
Sawyers, CL
Chinnaiyan, AM
Alimonti, A
Nelson, PS
Drake, CG
Van Allen, EM
de Bono, JS
Rescigno, P
Liu, D
Yuan, W
Carreira, S
Lambros, MB
Seed, G
Mateo, J
Riisnaes, R
Mullane, S
Margolis, C
Miao, D
Miranda, S
Dolling, D
Clarke, M
Bertan, C
Crespo, M
Boysen, G
Ferreira, A
Sharp, A
Figueiredo, I
Keliher, D
Aldubayan, S
Burke, KP
Sumanasuriya, S
Fontes, MS
Bianchini, D
Zafeiriou, Z
Teixeira Mendes, LS
Mouw, K
Schweizer, MT
Pritchard, CC
Salipante, S
Taplin, M-E
Beltran, H
Rubin, MA
Cieslik, M
Robinson, D
Heath, E
Schultz, N
Armenia, J
Abida, W
Scher, H
Lord, C
D'Andrea, A
Sawyers, CL
Chinnaiyan, AM
Alimonti, A
Nelson, PS
Drake, CG
Van Allen, EM
de Bono, JS
Document Type
Journal Article
Date
2018-10-01
Date Accepted
2018-07-10
Abstract
BACKGROUND: Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. METHODS: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed. RESULTS: Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT. CONCLUSION: These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC. FUNDING: We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.
Citation
The Journal of clinical investigation, 2018, 128 (10), pp. 4441 - 4453
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics