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

Integrin CD11b activation drives anti-tumor innate immunity

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy

Myeloid Stat3 promotes formation of colitis-associated colorectal cancer in mice

Myeloische Zellen mit einer Deletion von Stat3 fördern anti - Tumor - Antworten von NK- und T-Zellen, aber es ist noch nicht bekannt, ob dieser "Crosstalk" die Entstehung von körpereigenen Tumoren beeinflusst. Wir haben Stat3 in murinen myeloischen Zellen deletiert (STAT3dm) und den Effekt auf die Entwicklung von körpereigenen kolorektalen Tumoren (CRCs) untersucht. Die Bildung von Azoxymethane/Dextransulfate (AOM/DSS)-induzierten kolorektalen Tumoren war in STAT3dm Mäusen starkt reduziert. Genexpressionsanalysen zeigten eine starke Aktivierung von T-Zellen im Stroma von STAT3dm CRCs. Weiters konnten STAT3dm Mäuse das Wachstum von transplantierten MC38 kolorektalen Tumorzellen, die bekannterweise von T-Zellen getötet werden, besser kontrollieren. Aus diesen Daten können wir schliessen, dass myeloische Zellen ohne Stat3 die Bildung von kolorektalen Tumoren hauptsächlich durch "Cross-activation" von T-Zellen kontrollieren. Interessanterweiser zeigten die wenigen CRCs, die in STAT3dm Mäusen entstehen, eine erhöhte Stromalisierung bei gleicher Tumorgrösse. Dies weist darauf hin, dass diese Tumore Wege gefunden haben, der gesteigerten "Tumor Surveillance" zu entkommen. Weiters konnten wir feststellen, dass der Stat3 Signalweg in CRCs von STAT3dm Mäusen konstitutiv aktiviert ist. Die Aktivierung von Stat3 ist in einem Mechanismus, der "Immune evasion" genannt wird, impliziert und stellt ein mögliches Target zur Vorbeugung von Tumorrezidiven dar.Deletion of Stat3 in myeloid cells induces anti-tumor activities of NK and T cells, interfering with tumor growth and metastasis. To investigate the effect of myeloid Stat3 ablation in autochtonous tumors, we used the Stat3 Lysm-Cre mouse model to generate STAT3dm mice and induced colitis associated colorectal cancer (CRC) employing the Azoxymethane/Dextransulfate (AOM/DSS) protocol. In STAT3dm mice, the formation of AOM/DSS-induced CRCs was strongly reduced compared to STAT3wt control mice. Gene expression profiling showed strong induction of T cell activities in the tumormicroenvironment (TME) of STAT3dm tumors. Also the growth of transplanted MC38 adenocarcinoma cells, which is controlled in a T cell-dependent manner, was reduced in STAT3dm host mice. These data suggest that myeloid cells devoid of Stat3 supress CRC formation through cross activation of T cells. Notably, the few AOM/DSS-induced CRCs that formed in STAT3dm mice displayed increased stromalization but had a similar size as tumors formed in STAT3wt mice. This indicates that CRCs in STAT3dm mice have developed mechanisms to escape enhanced tumor immune surveillance. Moreover, CRCs in STAT3dm mice displayed upregulation of Stat3 signaling, a known mechanism of immune evasion. Targeting Stat3 might be a valuable therapeutic strategy to prevent tumor relapse.Paulina PathriaAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWird erscheinen in: Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice. 2015, OncoimmunologyWien, Med. Univ., Diss., 2015OeBB(VLID)171470

Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression.

Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 "don't eat me" signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. SIGNIFICANCE: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC

Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression.

Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function. Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin αvβ3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting αvβ3 (LM609) exploited the coenrichment of αvβ3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of αvβ3-expressing tumor cells despite their expression of the CD47 "don't eat me" signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-αvβ3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drug-resistant cancers. SIGNIFICANCE: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets αvβ3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC

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