Chimeric Amino Acid Rearrangements as Immune Targets in Prostate Cancer
Posted May 23, 2018
Julian J. Lum, PH.D., BC Cancer
While cancer immunotherapy has shown remarkable success in some cancers, prostate cancer (PCa) seems to be refractory. Dr. Julian Lum and his colleagues at BC Cancer wanted to find ways to overcome this barrier by identifying unique characteristics of PCa that could be targeted by the immune system. It is known that PCas contain types of mutation called gene-fusions, which are relatively rare in other epithelial cancers. These gene-fusions in turn give rise to unique features called chimeric amino acid sequences (CASQ). Dr. Lum and his colleagues hypothesized that CASQ sequences could serve as unique bar codes that the immune system can see and recognize as foreign.
With the support from a FY14 PCRP Exploration - Hypothesis Development Award, Dr. Lum and his multidisciplinary team of genomics and bioinformatics experts started by using highly sophisticated computational tools to identify all the possible CASQ sequences and decipher individual gene-fusions of human prostate tumors. They found that all of the intermediate/high-risk patient tumors carried these mutations, whereas only 69% of the low-risk patient tumors were found to have gene-fusions. Upon further investigation, they were surprised to find that as the cancer progressed, more mutations accumulated and there were signs that the immune system was getting shut off as a potential way for tumors to hide from detection by the immune system. These findings open up a potential new avenue to use gene-fusions as an immunotherapy target for PCa.
In the next phase of their work, Dr. Lum is validating these results in a larger set of patients and applying a streamlined approach to quickly verify which gene-fusions can be targeted in order to activate the immune system. Dr. Lum notes, “We want to know why these mutations accumulate and seem to shut off the immune system. If this is true, we could potentially target these mutations using the immune system to turn the cancer on itself”. Ultimately, Dr. Lum intends that this work will lead to the development of personalized, tailor-made immunotherapies created based on a patient’s gene-fusion profile for the treatment of PCa.
Gene fusions and predicted chimeric antigen sequence (CASQ)-derived epitopes are associated with predictions of immune cell infiltration. This analysis depicts the predicted immune cell infiltrate levels and immunological parameters for both the low- and the intermediate/high-risk cohorts. Colored annotation tracks represent patient characteristics, such as PSA level, age at diagnosis, Gleason score, log-predicted total tumor fusions, and predicted CASQ epitopes. In general, patients with strong expression of cytolytic immune genes harbored less tumor fusions and predicted CASQ epitopes, while patients with immune regulatory and Th2 expression signatures had more tumor fusions and predicted CASQ epitopes.
Kalina JL, Neilson DS, Lin YY, et al. 2017. Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T cell Epitopes & Immune Signatures in a Subset of Prostate Cancer, Clinical Cancer Res.
Last updated Thursday, October 8, 2020