The project of Prof. Jan Dumanski with the funding from National Science Centre under OPUS call

26.11.2023

Prof. Jan Dumanski, the Director of the3PLAB, obtained grant in the NZ2 category of the OPUS 25 NCN Narodowe Centrum Nauki and got his project ranked on 1st place in NZ2. The project will be carried out in cooperation with Prof. Natalia Rozwadowska from the Instytut Genetyki Człowieka PAN.

Loss of chromosome Y (LOY) is a common post-zygotic mutation (also called somatic), frequently observed in the cells of hematopoietic system in aging men. It is associated with increased mortality and various age-related diseases, including colorectal cancer (CRC) and prostate cancer (PRC). Our unpublished findings reveal that in CRC patients, circulating and tumor-infiltrating CD4+ T regulatory cells (Tregs) exhibit the highest LOY levels among leukocytes, accompanied by upregulated expression of immunosuppressive genes, indicating potential implications for immune regulation in cancer.

This project aims to investigate the causal involvement of LOY in cancer development, focusing on specific immune cell subpopulations (Tregs, MDSCs, CTLs, and Th) in both circulating and tumor micro-environments (TME) of colorectal cancer (CRC) and prostate cancer (PRC) patients. The study involves a comprehensive analysis of 60 new cases, expanding on previous findings to enhance statistical power. The research includes sorting seven leukocyte fractions, confirmation of LOY status using droplet-digital-PCR, transcriptomic profiling, and innovative in vitro modeling of LOY using CRISPR/Cas9 in human Treg-cells, along with functional evaluation in co-culture models of colon and prostate cancer cell lines. Collaboration with Prof. Natalia Rozwadowska from the Institute of Human Genetics, Polish Academy of Science will contribute valuable expertise, and validation will be performed using public databases with single-cell RNAseq data from various cancer types.

We hope to reveal the role of LOY in intensifying features the immuno-suppressive characteristics of Tregs, MDSCs, and potentially other cells in TME. Given LOY’s impact on immune gene dysregulation, it may influence the expression of markers associated with the efficacy of immunotherapy, highlighting a potential link between LOY in TME-infiltrating cells and suboptimal responses to immunotherapy.

Full results of grant contest can be found at https://www.ncn.gov.pl/konkursy/wyniki/2023-11-23-opus25-preludium22