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Targeting oncogene-dependent TIM-3 induces T cell reprogramming thereby enhancing graft-versus-leukemia immunity - scRNAseq

ABSTRACT: We use a mouse model for AML treatment in mice, based on injection of WEHI-3B AML cells followed by allogeneic transplantation of bone marrow and T cells. Allogeneic donor T cells will elicit anti-leukemic GVL effect. We want to decipher the importance of TIM-3 expression on T cells, therefore we used donor BM and donor T cells that contains a deletion for TIM-3 in CD8+ T cells (Havcr2fl/fl;E8icre/+). We performed single cell RNA sequencing and compared T cells isolated from Havcr2fl/fl;E8icre/+ or Havcr2fl/fl (control).

ORGANISM(S): Mus musculus

PROVIDER: GSE242334 | GEO | 2024/07/24

REPOSITORIES: GEO

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Project description:Exhaustion markers are expressed by T lymphocytes in Follicular Lymphoma (FL). Through these, TIM-3 has been recently identified as a poor pronostic factor when expressed by FL CD4+ T cells. Before this study, there was no molecular characterization of unstimulated CD8+ T cells, expressing - or not - TIM-3. We used microarrays to compare the global gene expression profile between CD8+TIM-3+ T cells and CD8+TIM-3- T cells freshly sorted from follicular lymphoma biopsies. Abstract from the associated publication: Up-regulation of T-cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+ T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+ T cells was observed by phospho-flow analysis. Finally, short relapse free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.

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Targeting oncogene-dependent TIM-3 induces T cell reprogramming thereby enhancing graft-versus-leukemia immunity - scRNAseq

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