Biology subjects

Nater, M.

Publications and source records attributed to Nater, M..

6 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

An oncoembryology approach uncovers SoxC-driven regulation of colon development and cancer

Reactivated embryonic programs are associated with cancer progression, yet their role and regulatory mechanisms remain poorly understood. In this study, we introduce oncoembryology, an approach that systematically compares embryonic and cancerous tissues to identify shared molecular programs and assess their functional relevance in disease. Applying this strategy to colorectal cancer, we identified SoxC transcription factors (Sox4, Sox11, Sox12) as critical regulators of both embryonic development and tumorigenesis. SoxC transcription factors regulate diverse downstream targets, including Tead2, Mdk, and Klf4, thereby regulating crucial steps of colon development. Abrogating SoxC function in murine models reduced tumor growth and prevented liver metastasis. Concordantly, a SoxC-driven oncoembryonic gene signature correlated with poor survival in colorectal cancer patients, underscoring the therapeutic potential of targeting SoxC-regulated pathways in cancer treatment.

cancer biology↗

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↗

bioRxiv2020

Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and non-redundant action of two innate lymphocyte subpopulations, conventional NK cells (cNKs) and tissue-resident type I Innate Lymphoid Cells (trILC1s), is essential for anti-metastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 control metastatic seeding, whereas cNKs restrain outgrowth. The antimetastatic activity of cNKs is regulated in a tumor type-specific fashion. Thereby, individual cancer cell lines orchestrate the emergence of cNK subsets with unique phenotypic and functional traits. Understanding cancer-cell- as well as innate-cell-intrinsic factors will allow the exploitation of hepatic innate cells for development of novel cancer therapies. SignificanceInnate lymphoid cells hold great promise for the treatment of metastases. Development of effective therapies based on these versatile immune cells, however, is hampered by our limited knowledge of their behavior in the metastatic niche. Here, we describe that defense against liver metastasis requires the collaboration between two innate lymphocyte subsets, conventional NK cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s). We show that different cancers generate their own particular metastatic niche inducing specific changes in cNKs and trILC1s. Further, we uncover specific cNK subsets that can be manipulated to improve their anti-metastatic potential. Our work contributes to understanding how cancer-specific factors and hepatic innate lymphocytes exert mutual influence and how this can be exploited for therapeutic purposes. HighlightsO_LIcNKs and trILC1s collaborate to control hepatic metastasis C_LIO_LItrILC1s restrict seeding and cNKs control outgrowth of cancer cells in the liver C_LIO_LIIndividual cancer cell lines orchestrate a distinct metastatic niche C_LIO_LIThe metastatic niche dictates the phenotype and function of cNKs C_LI

immunology↗