Search

Summary: Naturally derived regulatory T (Treg) cells are characterized by stable expression of the transcription factor Foxp3 and characteristic epigenetic imprinting at the Foxp3 gene locus. Here, we found that enhancing nuclear factor (NF)-κB activity via a constitutive active inhibitor of κB kinase β (IKKβ) transgene in T cells led to increased number of Foxp3+ cells in the thymus and can rescue Foxp3 expression in thymocytes deficient in other pleiotropic signaling molecules. Enhancing the signal strength of the NF-κB pathway also induced Foxp3 expression in otherwise conventionally selected T cells. NF-κB directly promoted the transcription of Foxp3, and upon T cell receptor (TCR) stimulation, c-Rel, a NF-κB family member, bound to Foxp3 enhancer region, which is specifically demethylated in natural Treg cells. Hence, NF-κB signaling pathway is a key regulator of Foxp3 expression during natural Treg cell development. [Copyright &y& Elsevier]

Summary: Immune tolerance against enteric commensal bacteria is important for preventing intestinal inflammation. Deletion of phosphoinositide-dependent protein kinase 1 (Pdk1) in T cells via Cd4-Cre induced chronic inflammation of the intestine despite the importance of PDK1 in T cell activation. Analysis of colonic intraepithelial lymphocytes of PDK1-deficient mice revealed markedly increased CD8α+ T cell receptor (TCR)γδ+ T cells, including an interleukin-17 (IL-17)-expressing population. TCRγδ+ T cells were responsible for the inflammatory colitis as shown by the fact that deletion of Tcrd abolished spontaneous colitis in the PDK1-deficient mice. This dysregulation of intestinal TCRγδ+ T cells was attributable to a reduction in the number and functional capacity of PDK1-deficient T regulatory (Treg) cells. Adoptive transfer of wild-type Treg cells abrogated the spontaneous activation and proliferation of intestinal TCRγδ+ T cells observed in PDK1-deficient mice and prevented the development of colitis. Therefore, suppression of intestinal TCRγδ+ T cells by Treg cells maintains enteric immune tolerance. [ABSTRACT FROM AUTHOR]

Summary: Inhibition of the transcription factor nuclear factor (NF)-κB activity leads to a reduction in numbers of CD8+ single-positive (SP) thymocytes, suggesting a selective role for NF-κB in these cells. To further explore the role of NF-κB in SP thymocytes, we utilized transgenic models that allowed either inhibition or activation of NF-κB. We showed that activation of NF-κB played an important role in the selection of major histocompatibility complex (MHC) class I-restricted CD8+ T cells. Surprisingly, NF-κB was not activated in positively selected CD4+ thymocytes, and inhibition of NF-κB did not perturb positive or negative selection of CD4+ cells. However, enforced activation of NF-κB via a constitutively active inhibitor of κB (IκB) kinase transgene led to a nearly complete deletion of CD4 cells by pushing positively selecting CD4+ cells into negative selection. These studies therefore revealed a surprising difference of NF-κB activation in CD4+ and CD8+ thymocytes and suggested that NF-κB contributes to the establishment of thresholds of signaling that determine positive or negative selection of thymocytes. [Copyright &y& Elsevier]

The existence of "leukemia-initiating cells" (LICs) in chronic lymphocytic leukemia (CLL) remains controversial due to the difficulty in isolating and identifying the tumor-initiating cells. Here, we demonstrate a microchannel electroporation (MEP) microarray that injects RNA-detecting probes into single live cells, allowing the imaging and characterization of heterogeneous LICs by intracellular RNA expression. Using limited-cell FACS sequencing (LC-FACSeq), we can detect and monitor rare live LICs during leukemogenesis and characterize their differential drug sensitivity. Disease-associated mutation accumulation in developing B lymphoid but not myeloid lineage in CLL patient hematopoietic stem cells (CLL-HSCs), and development of independent clonal CLL-like cells in murine patient-derived xenograft models, suggests the existence of CLL LICs. Furthermore, we identify differential protein ubiquitination and unfolding response signatures in GATA2 high CLL-HSCs that exhibit increased sensitivity to lenalidomide and resistance to fludarabine compared to GATA2 low CLL-HSCs. These results highlight the existence of therapeutically targetable disease precursors in CLL., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

By combining 6 druggable genome resources, we identify 6,083 genes as potential druggable genes (PDGs). We characterize their expression, recurrent genomic alterations, cancer dependencies, and therapeutic potentials by integrating genome, functionome, and druggome profiles across cancers. 81.5% of PDGs are reliably expressed in major adult cancers, 46.9% show selective expression patterns, and 39.1% exhibit at least one recurrent genomic alteration. We annotate a total of 784 PDGs as dependent genes for cancer cell growth. We further quantify 16 cancer-related features and estimate a PDG cancer drug target score (PCDT score). PDGs with higher PCDT scores are significantly enriched for genes encoding kinases and histone modification enzymes. Importantly, we find that a considerable portion of high PCDT score PDGs are understudied genes, providing unexplored opportunities for drug development in oncology. By integrating the druggable genome and the cancer genome, our study thus generates a comprehensive blueprint of potential druggable genes across cancers., Competing Interests: Declaration of interests L.Z. and X.H. report having received research funding from AstraZeneca, Bristol-Myers Squibb/Celgene, and Prelude Therapeutics. O.T. and H.M.C. are employees of AstraZeneca. R.H.V. is an inventor on a licensed patent relating to cancer cellular immunotherapy and receives royalties from Children's Hospital Boston for a licensed research-only monoclonal antibody., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies., Competing Interests: Declaration of Interests Drs. Lin Zhang, Xiaowen Hu, and Youyou Zhang report having received research funding from Bristol-Myers Squibb/Celgene and Prelude Therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Inhibition of the transcription factor nuclear factor (NF)-kappaB activity leads to a reduction in numbers of CD8(+) single-positive (SP) thymocytes, suggesting a selective role for NF-kappaB in these cells. To further explore the role of NF-kappaB in SP thymocytes, we utilized transgenic models that allowed either inhibition or activation of NF-kappaB. We showed that activation of NF-kappaB played an important role in the selection of major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Surprisingly, NF-kappaB was not activated in positively selected CD4(+) thymocytes, and inhibition of NF-kappaB did not perturb positive or negative selection of CD4(+) cells. However, enforced activation of NF-kappaB via a constitutively active inhibitor of kappaB (IkappaB) kinase transgene led to a nearly complete deletion of CD4 cells by pushing positively selecting CD4(+) cells into negative selection. These studies therefore revealed a surprising difference of NF-kappaB activation in CD4(+) and CD8(+) thymocytes and suggested that NF-kappaB contributes to the establishment of thresholds of signaling that determine positive or negative selection of thymocytes.

To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland--but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance--allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.