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S1: Unaltered tumor burden in colons of ACKR2-/-ApcMin/+ mice. S2: Delayed onset of tumor development in the small intestine of ACKR2-/-ApcMin/+ mice. S3. Decreased inflammatory markers in the distal intestine tumors of ACKR2-/-ApcMin/+ mice. S4. Elevated mast cell infiltration into microadenomas in ACKR2-/-ApcMin/+ mice. S5. Identification of BMMC. S6. Relative expression levels of chemokine receptors in BMMC. S7. Dinitrophenyl (DNP) induced calcium release in BMMC. S8. Analysis of CCR2 and CCR5 expression in immune cells from ACKR2-/- mice. S9. Uptake and MHC-1 mediated presentation of peptide antigens by mast cells. S10. Mast cell infiltration into ACKR2-/- tumors is not dependent on T cells. Supplemental Table 1: List of primers used for mouse genotyping. Supplemental Table 2: List of mouse Real Time PCR primer sequences.

The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (ApcMin/+) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2–/–ApcMin/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell–deficient ACKR2–/–SA–/–ApcMin/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2–/– mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8+ T cells. Mast cell–derived leukotriene B4 (LTB4) was found to be required for CD8+ T lymphocyte recruitment, as mice lacking the LTB4 receptor (ACKR2–/–BLT1–/–ApcMin/+) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB4/BLT1-regulated CD8+ T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors. Cancer Immunol Res; 6(3); 332–47. ©2018 AACR.

Subverting the host immune response to inhibit inflammation is a key virulence factor ofYersinia pestis. The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential forY. pestisto cause lethal infection, defining the mechanisms used byY. pestisto manipulate the inflammatory cascade is necessary to understand this pathogen’s virulence. While previous studies have established thatY. pestisactively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of inflammatory lipid mediator response during plague. Here we use in vivo lipidomics to define the synthesis of lipid mediators of inflammation within the lungs during pneumonic plague. Interestingly, while we observed an early cyclooxygenase response during pneumonic plague, there was a significant delay in the synthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid chemoattractant and activator of immune cells. Furthermore, in vitro studies with primary leukocytes from mice and humans further revealed thatY. pestisactively inhibited the synthesis of LTB4. Finally, usingY. pestismutants in the Ysc type 3 secretion system (T3SS) andYersiniaouter protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the synthesis of LTB4rapidly. However, the Yop effectors secreted through the same system effectively inhibit this host response. Together, these data demonstrate thatY. pestisactively inhibits the synthesis of LTB4, an inflammatory lipid, required for rapid recruitment of leukocytes to the site of infection.Author SummaryYersinia pestis, the bacteria that causes plague, targets the host’s innate immune response to inhibit inflammation. Because the generation of this non-inflammatory environment is required for infection, we are interested in mechanisms used byY. pestisto block inflammation. Lipid mediators are potent signaling molecules that regulate multiple host immune responses, including inflammation. While there have been studies on howY. pestisblocks the proteins that mediate inflammation, there is a gap in our understanding of the inflammatory lipid mediator response during plague. Here we show thatY. pestisinhibits the production of one of these critical lipid mediators, leukotriene B4, by host immune cells. Furthermore, we identify both the signals that induce LTB4production by leukocytes and the mechanisms used byY. pestisto inhibit this process. Together, these data represent the first comprehensive analysis of inflammatory lipids produced during plague and improve our current understanding of howY. pestismanipulates the host immune response to generate a permissive non-inflammatory environment required for bacterial colonization.

The biological activities of chemokine (C-C motif) ligand 2 (CCL2) are mediated via C-C chemokine receptor-2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In this study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the ApcMin/+ mouse model. Ablation of CCR2 in ApcMin/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2-/- ApcMin/+ mice exhibited significant reduction in the myeloid cell population and increased IFNγ producing T cells both in spleen and mesenteric lymph nodes (mLN) compared to ApcMin/+ mice. The CCR2-/- ApcMin/+ tumors showed significantly reduced levels of IL-17 and IL-23 and increased IFNγ and Granzyme B compared to ApcMin/+ tumors. Transfer of CCR2+/+ ApcMin/+ CD4+ T cells into Rag2-/- mice led to development of colitis phenotype with increased CD4+ T cells hyper proliferation and IL-17 production. In contrast, adoptive transfer of CCR2-/- ApcMin/+ CD4+ T cells into Rag2-/- mice failed to enhance colonic inflammation or IL-17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL-17 producing cells mediating tumor-promoting inflammation in addition to its role in migration of tumor associated macrophages. This article is protected by copyright. All rights reserved.

Independent reports note the significance of gut microbiota on lung disease severity; however, studies using murine models to define the role of the gut microbiome in pulmonary fibrosis progression are missing. We used the bleomycin murine model to quantify lung fibrosis in C57BL/6J mice housed in germ-free, animal biosafety level 1 (ABSL-1), or animal biosafety level 2 (ABSL-2) environments. Mice housed in gnotobiotic facilities are protected from bleomycin-induced pulmonary fibrosis, while ABSL-1 and ABSL-2 mice develop mild fibrosis and severe lung fibrosis, respectively. Metagenomic analysis of the gut microbiota revealed greater microbial diversity in ABSL-1 compared to ABSL-2 mice, with an increased presence of Lactobacilli and Bifidobacterium in ABSL-1 mice. Flow cytometric analysis of single-cell lung suspensions revealed enhanced IL-6/STAT3 /IL-17A signaling in CD4+ T cells of ABSL-2 mice, compared to ABSL-1 or germ-free mice. Fecal microbiota transplantation (FMT) of low microbial diverse stool (ABSL-2) into germ-free mice before bleomycin administration recapitulated the severe fibrosis phenotype, whereas FMT of ABSL-1 stool induced minimal fibrosis. These findings strongly support a causal role of the gut microbiota in augmenting pulmonary fibrosis severity after acute lung injury.

Depilatory creams are widely used to remove unwanted body hair, but people with sensitive skin are subject to depilatory-induced skin burn/inflammation. It remains unknown what makes their skin more sensitive than others. In this study, we show that epidermal fatty acid‒binding protein (E-FABP) expressed in the skin plays a critical role in promoting depilatory-induced acute skin inflammation in mouse models. Although a depilatory cream removed hair by breaking down keratin disulfide bonds, it activated cytosolic phospholipase A2, leading to activation of the arachidonic acid/E-FABP/peroxisome proliferator-activated receptor β signaling pathway in keratinocytes. Specifically, peroxisome proliferator-activated receptor β activation induced downstream targets (e.g., cyclooxygenase 2) and chemokine (e.g., CXCL1) production, which systemically mobilized neutrophils and recruited them to localize in the skin for acute inflammatory responses. Importantly, E-FABP deletion by CRISPR-Cas9 reduced cytosolic phospholipase A2/peroxisome proliferator-activated receptor β activation in keratinocytes, and genetic deletion of E-FABP protected mice from depilatory cream-induced neutrophil recruitment and skin inflammation. Our findings suggest E-FABP as a molecular sensor for sensitive skin by triggering depilatory-induced, lipid-mediated skin inflammatory responses.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder involving neurofibrillary tangles and amyloid plaques. The tau phosphorylation responsible for neurofibrillary tangles and amyloid deposition which causes plaques are both accelerated through the activity of 5-lipoxygenase (5-LO). In addition to these pathological pathways, 5-LO has also been linked to the neuro-inflammation associated with disease progression as well as to dysbiosis in the gut. Interestingly, gut dysbiosis itself has been correlated to AD development. Not only do gut metabolites have direct effects on the brain, but pro-inflammatory mediators such as LPS, BMAA and bacterial amyloids produced in the gut due to dysbiosis reach the brain causing increased neuro-inflammation. While microbial dysbiosis and 5-LO exert detrimental effects in the brain, the cause/effect relationship between these factors remain unknown. These issues may be addressed using mouse models of AD in the context of different knockout mice in the 5-LO pathway in specific pathogen-free, germ-free as well as gnotobiotic conditions.

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B4 (LTB4) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB4 and IL-1β in mouse macrophages, mast cells, and neutrophils. Phagosomes enclosing CS particles trigger the assembly of lipidosome in the cytoplasm, which is likely the primary source of CS-induced LTB4 production. Activation of the JNK pathway is essential for both CS-induced LTB4 and IL-1β production. Studies with bafilomycin-A1– and NLRP3-deficient mice revealed that LTB4 synthesis in the lipidosome is independent of inflammasome activation. Small interfering RNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB4 production. BI-78D3, a JNK inhibitor, abrogated CS-induced neutrophilic inflammation in vivo in an air pouch model. These results highlight an inflammasome-independent and JNK activation–dependent lipidosome pathway as a regulator of LTB4 synthesis and CS-induced sterile inflammation.

Yersinia pestis causes a rapid, lethal disease referred to as plague. Y. pestis actively inhibits the innate immune system to generate a noninflammatory environment during early stages of infection to promote colonization. The ability of Y. pestis to create this early noninflammatory environment is in part due to the action of seven Yop effector proteins that are directly injected into host cells via a type 3 secretion system (T3SS). While each Yop effector interacts with specific host proteins to inhibit their function, several Yop effectors either target the same host protein or inhibit converging signaling pathways, leading to functional redundancy. Previous work established that Y. pestis uses the T3SS to inhibit neutrophil respiratory burst, phagocytosis, and release of inflammatory cytokines. Here, we show that Y. pestis also inhibits release of granules in a T3SS-dependent manner. Moreover, using a gain-of-function approach, we discovered previously hidden contributions of YpkA and YopJ to inhibition and that cooperative actions by multiple Yop effectors are required to effectively inhibit degranulation. Independent from degranulation, we also show that multiple Yop effectors can inhibit synthesis of leukotriene B(4) (LTB(4)), a potent lipid mediator released by neutrophils early during infection to promote inflammation. Together, inhibition of these two arms of the neutrophil response likely contributes to the noninflammatory environment needed for Y. pestis colonization and proliferation.

The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (ApcMin/+) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2–/–ApcMin/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell–deficient ACKR2–/–SA–/–ApcMin/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2–/– mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8+ T cells. Mast cell–derived leukotriene B4 (LTB4) was found to be required for CD8+ T lymphocyte recruitment, as mice lacking the LTB4 receptor (ACKR2–/–BLT1–/–ApcMin/+) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB4/BLT1-regulated CD8+ T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors. Cancer Immunol Res; 6(3); 332–47. ©2018 AACR.

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B(4) (LTB(4)) plays an important role in neutrophilic inflammation that drives silicosis and promotes lung cancer. Here, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB(4) and IL-1β in mouse macrophages, mast cells and neutrophils. Phagosomes enclosing CS particles trigger the assembly of “lipidosome” in the cytoplasm that is likely the primary source of CS-induced LTB(4) production. Activation of JNK pathway is essential for both CS-induced LTB(4) and IL-1β production. Studies with bafilomycin-A1 and NLRP3 deficient mice revealed that LTB(4) synthesis in the lipidosome is independent of inflammasome activation. siRNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB(4) production. BI-78D3, a JNK inhibitor abrogated CS-induced neutrophilic inflammation in-vivo in an air pouch model. These results highlight an inflammasome independent and JNK activation dependent lipidosome pathway as a regulator of LTB(4) synthesis and CS-induced sterile inflammation.

The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.

Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-ras(LA1) mice, CS exposure markedly enhances the lung tumour burden and genetic deletion of leukotriene B4 receptor-1 (BLT1(-/-)) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1(-/-)K-ras(LA1) mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air-pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumour model, CS exposure results in rapid tumour growth and decreased survival that is attenuated in the absence of BLT1. These results suggest that the LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge may facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer.

Inflammation and infection are key promoters of colon cancer but the molecular interplay between these events is largely unknown. Mice deficient in leukotriene B4 receptor1 (BLT1) are protected in inflammatory disease models of arthritis, asthma and atherosclerosis. In this study, we show that BLT1−/− mice when bred onto a spontaneous tumor (ApcMin/+) model displayed an increase in the rate of intestinal tumor development and mortality. A paradoxical increase in inflammation in the tumors from the BLT1−/−ApcMin/+ mice is coincidental with defective host response to infection. Germ-free BLT1−/−ApcMin/+ mice are free from colon tumors that reappeared upon fecal transplantation. Analysis of microbiota showed defective host response in BLT1−/− ApcMin/+ mice reshapes the gut microbiota to promote colon tumor development. The BLT1−/−MyD88−/− double deficient mice are susceptible to lethal neonatal infections. Broad-spectrum antibiotic treatment eliminated neonatal lethality in BLT1−/−MyD88−/− mice and the BLT1−/−MyD88−/−ApcMin+ mice are protected from colon tumor development. These results identify a novel interplay between the Toll-like receptor mediated microbial sensing mechanisms and BLT1-mediated host response in the control of colon tumor development.

The G protein-coupled mu-opioid receptor (mu OR) mediates the physiological effects of endogenous opioid peptides as well as the structurally distinct opioid alkaloids morphine and etorphine. An intriguing feature of mu OR signaling is the differential receptor trafficking and desensitization properties following activation by distinct agonists, which have been proposed as possible mechanisms related to opioid tolerance. Here we report that the ability of distinct opioid agonists to differentially regulate mu OR internalization and desensitization is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the mu OR. Although both etorphine and morphine effectively activate the mu OR, only etorphine elicits robust mu OR phosphorylation followed by plasma membrane translocation of beta-arrestin and dynamin-dependent receptor internalization. In contrast, corresponding to its inability to cause mu OR internalization, morphine is unable to either elicit mu OR phosphorylation or stimulate beta-arrestin translocation. However, upon the overexpression of GRK2, morphine gains the capacity to induce mu OR phosphorylation, accompanied by the rescue of beta-arrestin translocation and receptor sequestration. Moreover, overexpression of GRK2 also leads to an attenuation of morphine-mediated inhibition of adenylyl cyclase. These findings point to the existence of marked differences in the ability of different opioid agonists to promote mu OR phosphorylation by GRK. These differences may provide the molecular basis underlying the different analgesic properties of opioid agonists and contribute to the distinct ability of various opioids to induce drug tolerance.

The uridine diphosphoglucose pyrophosphorylase (UDPGP1) gene of Dictyostelium discoideum is an excellent marker to study the pathways that control the expression of genes during development. We have previously shown that the UDPGP1 gene is regulated by exogenous cAMP acting on cell-surface cAMP receptors. Various steps in the signal transduction pathway between receptor stimulation and the induction of the gene can now be studied. Induction does not require the synthesis of intracellular cAMP, but does require new protein synthesis. By deletion and transformation with altered genes, two cis-acting sequences that are required for UDPGP1 expression have been identified. A GC-rich palindromic sequence located between -410 and -374 is essential for induction of the gene by extracellular cAMP, but not for its basal expression. A sequence element located between -374 and -337 is required for any basal expression of this gene. When the polarity of the palindromic sequence was reversed such that it resembled the H2K enhancer element, the gene could still be induced by exogenous cAMP. Two DNA binding activities were detected in gel mobility shift assays using a fragment containing both of the regulatory sequence elements of UDPGP1 gene. Transformation with a vector that resulted in the synthesis of anti-sense UDPGP1 RNA led to almost total elimination of the enzyme antigen and no detectable enzyme activity. However, these transformants developed normally, indicating that either UDPGP is not required for development or residual synthesis of UDPGP may be sufficient for normal development.

Leukotriene B4, a potent lipid mediator of inflammation acts through the G-protein coupled receptor, BLT1. The BLT1-/- mice displayed substantial protection in inflammatory disease models of arthritis, asthma and atherosclerosis. To examine the role of BLT1 in progression of cancers known to be promoted by inflammation, we crossed the BLT1-/- mice onto mice with a heterozygous mutation in the adenomatous polyposis coli (ApcMin/+) gene. The BLT1-/-ApcMin/+ mice demonstrated an increase in the rate of spontaneous intestinal tumor development and accelerated mortality. Unlike ApcMin/+ mice that develop mostly small intestinal tumors the BLT1-/-ApcMin/+ mice developed large colonic adenomas. Tumors from the BLT1-/-ApcMin/+ mice showed increased rates of proliferation, decrease in apoptosis and an increase in the expression of tumor promoting inflammatory markers such as TNF-α and CXCL1 and COX2 when compared to tumors from the ApcMin/+ mice. Microarray analysis of transcriptome showed that the paradoxical increase in inflammation in tumors from the BLT1-/-ApcMin/+ mice is coincidental with defective host response to infections. The expression of angiogenins, a class of antibacterial proteins was significantly reduced in tumors from BLT1-/-ApcMin/+ mice. Further, analysis of gut flora (by 16S ribosomal DNA sequences) identified major differences in microbiome colonizing the BLT1-/-ApcMin/+ and ApcMin/+ mice. BLT1-/-ApcMin/+ mice rederived and raised under germ-free conditions are completely protected from colon cancer development. To examine the role of Toll-like receptor mediated signaling events involved in tumor promotion in the absence of BLT1, we developed BLT1/MyD88 double deficient mice. The BLT1-/-MyD88-/- mice were highly susceptible to lethal neonatal infections indicating the cooperative interactions between TLR and leukotriene pathways in host response. These BLT1-/-MyD88-/- mice could be rescued by treatment with a broad-spectrum antibiotic. The MyD88-/-ApcMin/+ mice are highly protected from intestinal cancers. The BLT1-/-MyD88-/-ApcMin/+ mice are also highly protected indicating that BLT1-mediated host defense acts upstream of MyD88-mediated tumor promoting inflammation. While both BLT1 and MyD88 are important in host defense only the MyD88 but not BLT1 activated pathways are required to initiate tumor promoting inflammation. These results identify novel roles for gut microbiota in promoting colon cancer and for BLT1 in preventing the colon cancer development by shaping the gut microbiome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 411. doi:10.1158/1538-7445.AM2011-411

Immune system plays a dual role in cancer development and progression. Under conditions of chronic inflammation the repair response initiated by the immune system strongly promotes tumor growth. Epidemiological evidence of increased cancer incidence in organ transplant recipients and immune compromised individuals suggests a critical role for immune surveillance in keeping cancer under control. The cellular and molecular mechanisms that control tumor promoting chronic inflammation or tumor suppressing immune surveillance are unclear. Chemokines direct the migration of leukocytes to the sites of infection or injury and therefore are likely to play a central role in perpetuating tumor promoting chronic inflammation as well as orchestrating tumor eradicating immune surveillance. D6 is a chemokine decoy receptor and an effective scavenger of inflammatory CC-chemokines. D6-knockout (D6-/-) mice showed enhanced inflammation in different models including carcinogen-induced inflammation-promoted skin cancers. In this study, we show that D6-/- mice when bred onto mice with a heterozygous mutation in the adenomatous polyposis coli (ApcMin/+) gene demonstrated reduced intestinal tumor burden and increased survival. A decrease in tumor promoting inflammation is coincidental with increased mast cells and CD8+ T cell activation profiles in tumors from the D6-/-ApcMin/+ mice compared to ApcMin/+ mice. The D6-/-ApcMin/+ mice in the context of the lymphocyte deficient, Rag2-/-background (Rag2-/-D6-/-ApcMin/+), showed a significant increase in tumor burden that is reversed by the adoptively transferred CD8+ and/or CD4+T-lymphocytes from the D6-/-ApcMin/+ mice. Chemokine levels in serum and chemokine receptor expression patterns on lymphocytes from the ApcMin/+ and D6-/-ApcMin/+ mice and the Rag2-/-D6-/-ApcMin/+ mice undergoing adoptive transfer treatments identified the increased levels of ligand-receptor pairs of LTB4/BLT1, CCL2/CCR2, and CXCL9/CXCR3 being critical in promoting tumor suppressive immune surveillance in this spontaneous tumor model. These results show that inflammatory chemokines play a protective role against progression of intestinal cancers by immune surveillance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 800. doi:10.1158/1538-7445.AM2011-800