Biology subjects

Woodman, S. E.

Publications and source records attributed to Woodman, S. E..

3 recordsLinked to original sources

bioRxiv2026

The Y chromosome gene KDM5D restrains CD8+ T cell antitumor immunity through TCR and cholesterol-exhaustion programs

Sex differences in immunity shape cancer risk, autoimmunity, and responses to immunotherapy, yet the sex-chromosome genes that regulate antitumor T cell function remain incompletely defined. Here, we identify the Y chromosome-encoded KDM5D histone demethylase as a male-specific suppressor of CD8+ T cell antitumor immunity. In murine colorectal cancer (CRC) models, male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR{beta} abundance, and proximal TCR signaling relative to female CD8+ T cells. CRISPR-RNP-mediated KDM5D depletion in male CD8+ T cells enhanced effector function, increased TCR{beta} expression, augmented TCR signaling, and improved tumor control after adoptive transfer. Transcriptomic and functional analyses further linked KDM5D to cholesterol biosynthesis and exhaustion-associated programs, with KDM5D depletion reducing SREBP2/XBP1-associated cholesterol and exhaustion signatures. Correspondingly, human CRC single-cell analyses supported the clinical relevance of this axis, showing enrichment of exhausted and cholesterol-associated CD8+ T cell states in male tumors. Pharmacologic inhibition of cholesterol biosynthesis with lovastatin partially attenuated select exhaustion-associated markers in male CD8+ T cells and delayed tumor growth in vivo. Together, these findings define KDM5D as a sex chromosome-encoded regulator of male CD8+ T cell dysfunction and point to cholesterol-exhaustion programs as a potential therapeutic vulnerability in male CRC.

cancer biology↗

bioRxiv2022

Metabolic plasticity of T-cell therapies: multi-omic profiling of interacting human tumor-infiltrating lymphocytes and autologous tumor adoptive cell therapy

Adoptive cell therapy (ACT) based on ex vivo expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate durable antitumor responses even in heavily pretreated patients. However, only a subset of patients responds to ACT; efforts to identify correlates of response have focused on profiling the tumor or the TIL but rarely in an interactive environment. Interactive profiling can provide unique insights into the clinical performance of TILs since the fate, function, and metabolism of TILs are influenced by autologous tumor-derived factors. Here, we performed a suite of cell-sparing assays dubbed holistic analysis of the bioactivity of interacting T cells and autologous tumor cells (HABITAT). HABITAT profiling of TILs used for human ACT and their autologous tumor cells included function-based single-cell profiling by timelapse imaging microscopy in nanowell grids (TIMING); multi-omics using RNA-sequencing and proteomics; metabolite inference using genome-scale metabolic modeling, and pulse-chase assays based on confocal microscopy to profile the uptake and fate of fatty acids (FA). Phenotypically, the ACT TILs from both responders (Rs) and nonresponders (NRs) were comprised of predominantly effector memory T cells (TEM cells) and did not express a high frequency of programmed death ligand-1 (PD-L1) and showed no differences in TCR diversity. Our results demonstrate that while tumor cells from both Rs and NRs are efficient at uptaking FAs, R TILs are significantly more efficient at utilizing FA through fatty acid oxidation (FAO) than NR TILs under nutrient starvation conditions. While it is likely that lipid and FA uptake is an inherent adaptation of TIL populations to lipid-rich environments, performing FAO sustains the survival of TILs and allows them to sustain antitumor cytolytic activity. We propose that metabolic plasticity enabling FAO is a desirable attribute of human TILs for ACT leading to clinical responses.

immunology↗

bioRxiv2019

Bivalent and Broad Chromatin Domains Regulate Pro-metastatic Drivers in Melanoma

Chromatin deregulation is an emerging hallmark of cancer. However, the extent of epigenetic aberrations during tumorigenesis and their relationship with genetic aberrations are poorly understood. Using ChIP-sequencing for enhancers (H3K27ac and H3K4me1), promoters (H3K4me3), active transcription (H3K79me2) and polycomb (H3K27me3) or heterochromatin (H3K9me3) repression we generated chromatin state profiles in metastatic melanoma using 46 tumor samples and cell lines. We identified a strong association of NRAS, but not BRAF mutations, with bivalent states harboring H3K4me3 and H3K27me3 marks. Importantly, the loss and gain of bivalent states occurred on important pro-metastasis regulators including master transcription factor drivers of mesenchymal phenotype including ZEB1, TWIST1, SNAI1 and CDH1. Unexpectedly, a subset of these and additional pro-metastatic drivers (e.g. POU3F2, SOX9 and PDGFRA) as well as melanocyte-specific master regulators (e.g. MITF, ZEB2, and TFAP2A) were regulated by exceptionally wide H3K4me3 domains that can span tens of thousands of kilobases suggesting roles of this new epigenetic element in melanoma metastasis. Overall, we find that BRAF, NRAS and WT melanomas may use bivalent states and broad H3K4me3 domains in a specific manner to regulate pro-metastatic drivers. We propose that specific epigenetic traits - such as bivalent and broad domains - get assimilated in the epigenome of pro-metastatic clones to drive evolution of cancer cells to metastasis.

cancer biology↗