Immune-focused multi-omics analysis of prostate cancer: leukocyte Ig-Like receptors are associated with disease progression

ABSTRACT

Prostate cancer (PCa) immunotherapy has shown limited efficacy so far, even in advanced-stage cancers. The success rate of PCa immunotherapy might be improved by approaches more adapted to the immunobiology of the disease. The objective of this study was to perform a multi-omics analysis to identify immune genes associated with PCa progression to better characterize PCa immunobiology and propose new immunotherapeutic targets. mRNA, miRNA, methylation, copy number aberration, and single nucleotide variant datasets from The Cancer Genome Atlas PRAD cohort were analyzed after filtering for genes associated with immunity. Sparse partial least squares-discriminant analyses were performed to identify features associated with biochemical recurrence (BCR) in each type of omics data. Selected features predicted BCR with a balanced error rate (BER) of 0.20 to 0.51 in single-omics and of 0.05 in multi-omics analyses. Amongst features associated with BCR were genes from the Immunoglobulin Ig-like Receptor (LILR) family which are immune checkpoints with immunotherapeutic potential. Using Multivariate INTegrative (MINT) analysis, the association of five LILR genes with BCR was quantified in a combination of three RNA-seq datasets and confirmed with Kaplan-Meier analysis in both these and in an independent RNA-seq dataset. Finally, immunohistochemistry showed that a high number of LILRB1 positive cells within the tumors predicted long-term adverse outcomes. Thus, tumors characterized by abnormal expression of LILR genes have an elevated risk of recurring after definitive local therapy. The immunotherapeutic potential of these regulators to stimulate the immune response against PCa should be evaluated in pre-clinical models.

KEYWORDS:

• Prostate cancer
• biochemical recurrence
• multi-omics analysis
• leukocyte Ig-Like Receptors
• immunotherapy

Acknowledgments

The authors would like to thank Fan Mo and Antonio Hurtado-Coll for the preparation of the data from VPCC.

Disclosure statement

No potential conflicts of interest were disclosed.

Author contribution

BV, YF, AB, ML, and AD conceived the study. YF, AB, and AD supervised the study. BV performed all bioinformatics and statistical analyses. JL and PCB performed some bioinformatic analyses. OEM performed the analysis of housekeeping gene expression. OEM, XPL, HH, and VP were involved in the immunohistochemistry analyses. AB, ML, MLMM, PB, CC, YF, and AD interpreted data and provided advice. BV, AB, and ML wrote the manuscript. All authors critically reviewed the manuscript.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This research was realized with internal funds from the Laboratoire d’Uro-Oncologie Expérimentale. The production of RNA-seq data at VPCC was realized with funds from the Terry Fox Research Institute New Frontier Program Project Grant #1062.