Exploiting Retained Intron (RI)-Derived Neoepitopes for Innovative Prostate Cancer Immunotherapy
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) claims the lives of >32,000 American each year, and there are few effective treatment options for mCRPC patients. The next-generation antiandrogens such as Enzalutamide (Enza) and abiraterone acetate (AA) only extend patients’ lives by 3-4 months, even when used with chemotherapeutic agents or novel targeted therapeutics such as PARP inhibitors. Immunotherapies such as immune checkpoint inhibitors (ICI) are generally ineffective in PCa, mainly due to preexisting and therapy-induced immunosuppressive tumor microenvironment (TME) in most metastatic sites. Moreover, PCa is known to have low tumor mutational burden and low mutation rate (~0.5 per Mbp), and most driver mutations have low representations. These indolent genomic features and paucity of PCa-specific TAAs (tumor-associated antigens) and especially neoantigens (neoAgs) greatly contribute to the cold TME in mCRPC and to the lukewarm responses to ICIs. However, PCa has prevalent and pervasive abnormalities in their transcriptomes, i.e., the entire repertoire of RNA transcripts from their genomic DNA. A recent publication may have identified a unique vulnerability in aggressive mCRPC. When systematically mapping the mRNA alternative splicing (the process whereby different isoforms of one mRNA are made) landscape in the spectrum of PCa evolution, the authors in this study observed that the severity of splicing dysregulation correlates with PCa progression and that mCRPC is particularly sensitive to chemical inhibitors that interfere with the splicing process (Nat Commu. 2020). More surprisingly, the authors discovered intron retention (IR) as a consistent hallmark of PCa stemness and aggressiveness with mCRPC possessing the highest numbers of Retained Introns (RI). Normally, introns are removed (spliced out) during generation of mature RNA products, but in a peculiar way, mCRPC produces a high number of mRNA transcripts with RIs. Why does mCRPC have so abundant mRNA transcripts with RIs? More and more recent studies begin to link IR Program to development and stem cell functions and to cancer progression; of great interest, some studies suggest that many RIs in melanoma and colon cancer cells may be able to encode peptides that can bind MHC-I and potentially function as cancer neoantigens. Cancer neoantigens are cancer cell-specific markers that can engage the host immune system to kill cancer cells. Much inspired by these recent studies, in this project, we plan to systematically annotate the RIs in PCa and test the overarching hypothesis that some aggressive PCa-specific RIs are translated into peptides that can function as mCRPC-specific neoantigens. This EHDA project tackles two PCRP Overarching Challenges, define the biology of prostate cancer progression to lethal prostate cancer to reduce death and develop treatments that improve outcomes for men with lethal prostate cancer. Work here will provide the first evidence that some RIs in aggressive, Enza-refractory, and metastatic PCa can encode neoantigens to elicit specific T cell cytotoxicity. Our future goal is to translate this RI-neoAg discovery platform to PCa patients by developing personized neoantigen-specific vaccines and T cell therapies, which, together with ADT/Enza, should extend mCRPC patients’ survival by co-targeting bulk differentiated (AR-dependent) PCa cells and the aggressive, stem-like, highly plastic, and therapy-resistant PCa cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310108
Entities
People
- Dean Tang
Organizations
- United States Army