Biology subjects

Herbst, M.

Publications and source records attributed to Herbst, M..

4 recordsLinked to original sources

bioRxiv2024

Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells

Using a mouse tumor model with inducible cancer-cell-intrinsic cGAS expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This led to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of STING-expressing but not of STING-deficient CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhanced tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/620471v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@13b075borg.highwire.dtl.DTLVardef@601b49org.highwire.dtl.DTLVardef@19f58e4org.highwire.dtl.DTLVardef@84e8bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Pre-existing intratumoral stem-like CD8+ T-cells drive radiotherapy-induced tumor control

CD8+ T-cells are essential for spontaneous and therapy-induced restriction of tumor progression. Upon radiotherapy, these pre-existing CD8+ T-cells expand rapidly after their initial decline and are essential and sufficient for early tumor control. Stem-like CD8+ T-cells proliferate and differentiate into effector CD8+ T-cells in response to radiotherapy and are thus key determinants of therapy efficacy. Our findings highlight the critical role of intratumoral stem-like CD8+ T-cells in driving radiotherapy-induced anti-tumor immunity. Our study provides deeper insights into the dynamic behavior of CD8+ T-cells and their critical involvement in tumor control following radiotherapy.

immunology↗

bioRxiv2024

Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver

The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated cancer cells. Mechanistically, iNKT cells respond to disseminating cancer cells by producing the fibrogenic cytokines IL-4 and IL-13 in a TCR-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis.

immunology↗

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↗