Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice

Myeloid cells lacking STAT3 promote antitumor responses of NK and T cells but it is unknown if this crosstalk affects development of autochthonous tumors. We deleted STAT3 in murine myeloid cells (STAT3(Δm)) and examined the effect on the development of autochthonous colorectal cancers (CRCs). Formation of Azoxymethane/Dextransulfate (AOM/DSS)-induced CRCs was strongly suppressed in STAT3(Δm) mice. Gene expression profiling showed strong activation of T cells in the stroma of STAT3(Δm) CRCs. Moreover, STAT3(Δm) host mice were better able to control the growth of transplanted MC38 colorectal tumor cells which are known to be killed in a T cell-dependent manner. These data suggest that myeloid cells lacking STAT3 control formation of CRCs mainly via cross activation of T cells. Interestingly, the few CRCs that formed in STAT3(Δm) mice displayed enhanced stromalization but appeared normal in size indicating that they have acquired ways to escape enhanced tumor surveillance. We found that CRCs in STAT3(Δm) mice consistently activate STAT3 signaling which is implicated in immune evasion and might be a target to prevent tumor relapse

Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1

Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen

IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy

IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy

Correction: Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

The role of Stat1 in intestinal tumorigenesis

Maligne Tumore etablieren Mechanismen mit deren Hilfe sie der Überwachung des Immunsystems entkommen. Das neue Feld der Immuntherapie versucht jene Mechanismen zu reversieren, um die Tumorzellen für das angeborene und adaptive Immunsystem wieder detektierbar zu machen. Da dieser Therapieansatz bei der Behandlung des kolorektalen Karzinoms (KRK) nur bedingt erfolgreich ist, werden präklinische Studien benötigt um Resistenzmechanismen zu identifizieren. Indoleamin-2,3-Dioxygenase-1 (Ido1) ist ein Enzym, welches durch die Aktivierung verschiedener Signalwege in Tumor- und Stromazellen das Immunsystem daran hindert Tumore zu bekämpfen. In dieser Studie haben wir Ido1-exprimierende Zellen in intestinalen Krypten und Adenomen von Mäusen identifiziert. Ido1+ Zellen wurden abwechselnd mit Ido1- Zellen detektiert und ähnelten dem alternierenden Muster von sekretorischen Paneth-Zellen und Lgr5+ Stammzellen in den Krypten des Darms. Des Weiteren exprimierten Ido1+ Zellen einen Paneth-Zell Marker, Lysozym, weshalb wir sie paneth-ähnliche Zellen nennen. Die gezielte Deletion von Signal transducer and activator of transcription 1 (Stat1) in Zellen des intestinalen Epithels ging einher mit der Depletion dieser Ido+ paneth-ähnlichen Zellen und einer stark reduzierten Tumorgenese. Diese Tumore wiesen eine höhere Zahl an zytotoxischen T Zellen und weniger regulatorische T Zellen auf, im Gegensatz zu jenen Tumoren, welche Ido+ paneth-ähliche Zellen besaßen. In den Tumorzellen wurde weniger nukleär lokalisiertes -Catenin detektiert, was auf eine Reduktion des Wingless/Int-1 (Wnt) Signalweges hindeutet. Weiters konnten wir zeigen, dass die Differenzierung von Ido1+ paneth-ähnlichen Zellen vom unphosphorylierten und nicht vom klassischen, phosphorylierten Stat1 Signal abhänging ist. Korrelationen von Ido1, Stat1 und Lysozym in Datensätzen von KRK des "The Cancer Genome Atlas" (TCGA) zeigten, dass diese Zellen auch in Patienten vorhanden sind. Weiters konnten wir mittels immunhistochemischer Färbung Ido1+ Tumorepithelzellen in Patientenbiopsien nachweisen. Unsere Studien haben Ido1+ paneth-ähnliche Zellen in intestinalen Krypten und Adenomen identifiziert die dazu beitragen, den Tumor vor dem Immunsystem zu maskieren. Mit dieser Erkenntnis haben wir einen neuen Mechanismus in KRK definiert, der Tumoren hilft der Anti-Tumorüberwachung zu entkommen. Diese Zellen stellen ein potenzielles Ziel für die Immuntherapie dar.Tumors have developed a variety of mechanisms to escape innate and adaptive immune surveillance. Immunotherapy aims to revert these immunosuppressive effects and to sensitize tumors to immune attack. Especially in colorectal cancer (CRC), success of immunotherapy is limited. Only a minority of CRCs with microsatellite instability exhibit favorable response, due to the high number of neoantigens displayed. Consequently, identification of resistance mechanisms is of major importance for immunotherapy of CRC. Indoleamine-2,3-dioxygenase-1 (Ido1) is a potent inhibitor of anti-tumor immune surveillance due to various tumor cell-intrinsic and -extrinsic mechanisms. We discovered Ido1-expressing cells in the stem cell niche of intestinal crypts and in adenomas of mice. These Ido1-expressing cells alternated with Ido1-negative stem cells expressing Lgr5 in crypts of the small and large intestine, resembling the pattern of Paneth and Lgr5+ cells observed in the stem cell niche. Importantly, immunohistochemical stainings revealed coexpression of Ido1 and the Paneth cell marker lysozyme. Therefore, we entitled these cells Ido1-expressing paneth-related cells. Intestinal epithelial ablation of signal transducer and activator of transcription 1 (Stat1) abrogated Ido1-expressing paneth-related cancer cells which markedly interfered with intestinal tumorigenesis. Absence of this cell type favored the infiltration of cytotoxic T cells into the tumor and reduced intratumoral numbers of T regulatory cells. In addition to augmented immune surveillance, canonical Wingless/Int-1 (Wnt) signaling was strongly reduced, as indicated by decreased levels of nuclear -catenin. Furthermore, establishment of Ido1-expressing paneth-related cells was dependent on unphosphorylated Stat1 but not on canonical, phosphorylated Stat1 signaling. Analysis of "The Cancer Genome Atlas (TCGA)" data sets and staining of patient samples for Ido1 revealed corresponding cells in human colorectal tumors. Importantly, presence of these cells was of prognostic value in patients suffering from CRC. Our data identified Ido1-expressing paneth-related cells in intestinal crypts and adenomas. Additionally, we uncovered the role of Ido1-expressing paneth-related cancer cells in promotion of tumor immune escape as a new mechanism of immunosuppression in CRC. We suggest that targeting paneth-related tumor cells in colorectal cancers represents a potent option for immunotherapy.submitted by Jasmin SvinkaZusammenfassung in deutscher SpracheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität, Dissertation, 2017OeBB(VLID)192745

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3∆hc) aggravated liver damage and fibrosis in the Mdr2−/− (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3∆hc Mdr2−/− mice but the functional consequences of these processes in cholestatic liver injury remained unclear. Here, we show normal canalicular architecture and bile flow but increased amounts of bile acids in the bile of STAT3∆hc Mdr2−/− mice. Moreover, STAT3-deficient hepatocytes displayed increased sensitivity to bile acid-induced apoptosis in vitro. Since EGFR signaling has been reported to protect hepatocytes from bile acid-induced apoptosis, we generated mice with hepatocyte/cholangiocyte-specific ablation of EGFR (EGFR∆hc) and crossed them to Mdr2−/− mice. Importantly, deletion of EGFR phenocopied deletion of STAT3 and led to aggravated liver damage, liver fibrosis, and hyperproliferation of K19+ cholangiocytes. Our data demonstrate hepatoprotective functions of the STAT3-EGFR signaling axis in cholestatic liver disease

STAT1 is a sex‐specific tumor suppressor in colitis‐associated colorectal cancer

The interferon‐inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex‐specific STAT1 functions in colitis and colitis‐associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1∆IEC). Male but not female STAT1∆IEC mice were more resistant to DSS‐induced colitis than sex‐matched STAT1flox/flox controls and displayed reduced intraepithelial infiltration of CD8+ TCRαβ+ granzyme B+ T cells. Moreover, DSS treatment failed to induce expression of T‐cell‐attracting chemokines in intestinal epithelial cells of male but not of female STAT1∆IEC mice. Application of the AOM‐DSS protocol for induction of colitis‐associated CRC resulted in increased intestinal tumor load in male but not in female STAT1∆IEC mice. A sex‐specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell‐intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women. These data demonstrate that epithelial STAT1 is a male‐specific tumor suppressor in CRC of mice and humans

IDO1 + Paneth cells promote immune escape of colorectal cancer

Abstract: Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy