Biology subjects

Tallon de Lara, P.

Publications and source records attributed to Tallon de Lara, P..

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↗

bioRxiv2024

Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy

Metastases arise from disseminated cancer cells (DCCs) that detach from the primary tumor and seed distant organs. There, quiescent DCCs can survive for an extended time, a state referred to as metastatic dormancy. The mechanisms governing the induction, maintenance, and awakening from metastatic dormancy are unclear. We show that the differentiation of dormancy-inducing CD8+ T cells requires CD4+ T cell help, and that IFN{gamma} directly induces dormancy in DCCs. The maintenance of metastatic dormancy, however, is independent of T cells. Instead, awakening from dormancy requires an inflammatory signal, and we identified CD4+ T cell-derived IL- 17A as an essential wake-up signal for dormant DCCs in the lungs. Thus, the induction and awakening from metastatic dormancy require an external stimulus, while the maintenance of dormancy does not rely on the continuous surveillance by lymphocytes.

immunology↗

bioRxiv2020

CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer

Some breast tumors metastasize aggressively whereas others remain in a state of metastatic dormancy for months or even years. The mechanism governing such metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identified a discrete population of CD39+PD-1+CD8+ T cells present both in primary tumors and in dormant metastasis, which was hardly found in aggressively metastasizing tumors. Using blocking antibodies, we found that dormancy depended on TNF and IFN{gamma}. Of note, immunotherapy reduced the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevented metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not of total CD8+ T cells correlated with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Furthermore, density of CD39+PD-1+CD8+ T cells may serve as a novel biomarker and may serve as a potential immunotherapy target. Thus, we discovered that a primary breast tumor primes a systemic, CD39+PD-1+CD8+ T cell response that is essential for metastatic dormancy in the lungs.

cancer biology↗