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- Mattisson, Jonas, 1994-, et al.
(författare)
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Loss of chromosome Y in regulatory T cells
- 2024
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Ingår i: BMC Genomics. - : BioMed Central (BMC). - 1471-2164. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples.ResultsRegulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells.ConclusionsHere, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.
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| 2. |
- Mattisson, Jonas, 1994-
(författare)
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The role of hematopoietic chromosome Y loss in health and disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation, and affected men have increased risk for all major causes of death, including cardiovascular diseases and cancer. As a male specific mutation, it helps explain why men live shorter lives than women. However, the causality is debated, and contrasting models have been proposed to explain how Y loss in blood could be linked with disease in other organs. In this thesis, I provide results contributing to this debate.In Paper I, we identify 156 loci associated with genetic susceptibility for mLOY. Enrichment of loci involved in processes such as cell-cycle regulation and cancer susceptibility suggest that mLOY could be viewed as a barometer of genomic instability. In Paper II, we used the mLOY-associated variants identified in Paper I to calculate a PRS for mLOY in an independent cohort. We found that men with high PRS displayed a five-fold increased risk in an age dependent manner.In Paper III, we showed that mLOY and CHIP driving SNVs often co-occur in leukocytes. Considering that they share clinical manifestations, further studies are necessary to elucidate how these mutations contributes to disease risk. In Paper IV, we studied transcriptional effects of mLOY in leukocytes and identified almost 500 dysregulated autosomal genes, varying between cell types. We also report that mLOY in specific leukocytes might be linked with different types of disease. In Paper V, regulatory T cells are shown to be affected with Y loss to a greater extent than other CD4+ T lymphocytes. We propose that mLOY might drive T lymphocytes towards the regulatory phenotype, known to exhibit immunosuppressive functions. In Paper VI, we used CITE-seq to show that expression and cell surface abundance of the immunoprotein CD99 is lower in leukocytes with Y loss. This finding provides a possible explanation how mLOY could influence normal immune response, since CD99 is essential is for the mobility and cell-to-cell interactions of leukocytes. In Paper VII, it is shown that hematological mLOY cause disease directly in other organs. Mice with mLOY was shown to have a reduced survival, increased fibrosis and cardiac dysfunction, while men in UK biobank with mLOY in blood was found to die from diseases of the circulatory system in a dose dependent manner. Treatment with TGFβ1-inhibitors could restore cardiac function in mLOY-mice. Together, the presented results show that mLOY both reflect genomic instability overall, while also causing disease directly.
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| 3. |
- Wójcik, Magdalena, et al.
(författare)
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Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4 + T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY (22%) in comparison to CD4 + T-lymphocytes and cytotoxic CD8 + T-lymphocytes. LOY score using scRNA-seq was also linked to higher expression of PDCD1, TIGIT and IKZF2 in Tregs. PDCD1 and TIGIT encode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.
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