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Peutz–Jeghers Syndrome (PJS) causes benign polyps in the gut and a higher risk of several cancers caused by mutations in the tumor suppressor gene STK11 , which encodes liver kinase B1 (LKB1). LKB1's role in this disease is thought to be related to its tumor suppressor function. Now, Poffenberger et al. show that the T cell–specific heterozygous deletion of Stk11 is sufficient to reproduce PJS symptoms in mice (see the Perspective by Hollstein and Shaw). Polyps in mice and humans are characterized by immune cell infiltration, enhanced STAT3 signaling, and increased levels of inflammatory cytokines such as interleukin-6 (IL-6). Targeting STAT3 signaling, IL-6, or T cells ameliorated the polyps, suggesting potential therapies for this disease. Science , this issue p. 406 ; see also p. 332 T cell–mediated inflammation promotes Peutz–Jeghers syndrome. Germline mutations in STK11 , which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LT het mice) is sufficient to promote GI polyposis. Polyps from LT het mice, Stk11 +/− mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11 +/ − animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

Colorectal cancer (CRC) is a significant health issue, with notable incidence rates in Norway. The immune response plays a dual role in CRC, offering both protective effects and promoting tumor growth. This research aims to provide a detailed screening of immune-related genes and identify specific genes in CRC and adenomatous polyps within the Norwegian population, potentially serving as detection biomarkers. The study involved 69 patients (228 biopsies) undergoing colonoscopy, divided into CRC, adenomatous polyps, and control groups. We examined the expression of 579 immune genes through nCounter analysis emphasizing differential expression in tumor versus adjacent non-tumorous tissue and performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) across patient categories. Key findings include the elevated expression of CXCL1, CXCL2, IL1B, IL6, CXCL8 (IL8), PTGS2, and SPP1 in CRC tissues. Additionally, CXCL1, CXCL2, IL6, CXCL8, and PTGS2 showed significant expression changes in adenomatous polyps, suggesting their early involvement in carcinogenesis. This study uncovers a distinctive immunological signature in colorectal neoplasia among Norwegians, highlighting CXCL1, CXCL2, IL1B, IL6, CXCL8, PTGS2, and SPP1 as potential CRC biomarkers. These findings warrant further research to confirm their role and explore their utility in non-invasive screening strategies.

Little is known about the immunoediting process in precancerous lesions. We explored this aspect of benign colorectal adenomas with a descriptive analysis of the immune pathways and immune cells whose regulation is linked to the morphology and size of these lesions. Two series of polypoid and nonpolypoid colorectal adenomas were used in this study: 1) 84 samples (42 lesions, each with matched samples of normal mucosa) whose gene expression data were used to quantify the tumor morphology- and size-related dysregulation of immune pathways collected in the Molecular Signature Database, using Gene Set Enrichment Analysis; 2) 40 other lesions examined with immunohistochemistry to quantify the presence of immune cells in the stromal compartment. In the analysis of transcriptomic data, 429 immune pathways displayed significant differential regulation in neoplasms of different morphology and size. Most pathways were significantly upregulated or downregulated in polypoid lesions versus nonpolypoid lesions (regardless of size). Differential pathway regulation associated with lesion size was observed only in polypoid neoplasms. These findings were mirrored by tissue immunostaining with CD4, CD8, FOXP3, MHC-I, CD68, and CD163 antibodies: stromal immune cell counts (mainly T lymphocytes and macrophages) were significantly higher in polypoid lesions. Certain markers displayed significant size-related differences regardless of lesion morphology. Multivariate analysis of variance showed that the marker panel clearly discriminated between precancerous lesions of different morphologies and sizes. Statistical analysis of immunostained cell counts fully support the results of the transcriptomic data analysis: the density of infiltration of most immune cells in the stroma of polypoid precancerous lesions was significantly higher than that observed in nonpolypoid lesions. Large neoplasms also have more immune cells in their stroma than small lesions. Immunoediting in precancerous colorectal tumors may vary with lesion morphology and stage of development, and this variability could influence a given lesion's trajectory to cancer.

Purpose Dysregulation of toll-like receptors (TLR) signaling can result in chronic inflammatory and over-exuberant repair responses. The aim of this study was to investigate the expression and clinical relevance of TLR in colorectal polyps. Methods The expression levels of six TLR were analyzed in 70 patients with different histological types of colorectal polyps, 38 of which developed colorectal carcinoma (CC). These analyses were performed by real-time polymerase chain reaction, western blot, and immunohistochemistry. Results TLR9 expression was higher in hyperplastic or adenomatous polyps compared to other polyp types. Hyperplastic polyps also showed increased TLR7 levels compared to the other polyp types. TLR7 expression was lower in both hyperplastic and tubulovillous adenoma polyps from patients who developed CC. TLR9 expression was decreased in hyperplastic and villous polyps from patients who developed CC. Conclusions Our findings suggest a possible protective role of TLR expression against malignant transformation in the colorectal mucosa. TLR may represent a pathological marker of CC risk in colorectal polyps. The role of these factors in the pathology of colorectal polyps deserves further investigation.

Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is associated with the development of hundreds of adenomas in the small and large intestines of individuals starting in the teenage years with a near 100% risk of developing colorectal cancer by adulthood. Eventually polyps develop throughout the gastrointestinal tract. Chemoprevention approaches have been somewhat successful in reducing polyp burden, but have not reduced the risk of the development of colorectal cancer or other cancers. The lack of efficacy of more standard drug approaches may be due to limited exposure to the agent only to specific periods while the drug is being metabolized, limited drug penetrance in the colon, and patient adherence to daily dosing and drug side effects. The success of immune therapy for the treatment of invasive cancer has led to research focused on the use of immune based approaches for polyp control in FAP, specifically polyp directed vaccines. Vaccines targeting antigens expressed in FAP lesions may be a superior method to control polyp burden and prevent disease progression as compared to classic chemoprevention drugs. A limited number of vaccines can be administered over a short period of time to generate a lasting immune response. Appropriately primed antigen specific T-cells can traffic to any site in the body where antigen is expressed, recognize, and eliminate the antigen expressing cell. Immunologic memory will allow the immune response to persist and the specificity of the immune response will limit toxicity to the targeted polyp. This review will examine the current state of vaccines directed against FAP lesions and highlight the challenges and opportunities of translating vaccines for cancer interception in FAP to the clinic.

PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli ( APC ) gene lead to colonic epithelial cell resistance to CD8 + T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition.

Background Peutz‐Jeghers syndrome (PJS), is a rare autosomal dominant hereditary disease characterized by an elevated risk of various cancers. Serine/Threonine Kinase 11 (STK11) gene is a major tumor suppressor crucial for immune evasion with and beyond tumorigenic cells. It has garnered increasing attention in the realm of oncology treatment, particularly in the context of immunotherapy development. Objective This study aimed to assess the suitability of polyps obtained from individuals with PJS, resulting from germline STK11 deficiency, for immunotherapy. Additionally, we seek to identify potential shared mechanisms related to immune evasion between PJS polyps and cancers. To achieve this, we examined PJS polyps alongside familial adenomatous polyposis (FAP) and sporadic polyps. Methods Polyps were compared among themselves and with either the paracancerous tissues or colon cancers. Pathological and gene expression profiling approaches were employed to characterize infiltrating immune cells and assess the expression of immune checkpoint genes. Results Our findings revealed that PJS polyps exhibited a closer resemblance to cancer tissues than other polyps in terms of their immune microenvironment. Notably, PJS polyps displayed heightened expression of the immune checkpoint gene CD80 and an accumulation of myeloid cells, particularly myeloid‐derived suppressor cells (MDSCs). Conclusion The findings suggest an immunobiological foundation for the increased cancer susceptibility in PJS patients, paving the way for potential immune therapy applications in this population. Furthermore, utilizing PJS as a model may facilitate the exploration of immune evasion mechanisms, benefiting both PJS and cancer patients.

Diffuse large B cell lymphoma (DLBCL) is a common and fatal hematological malignancy. Long noncoding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers. Novel lncRNA biomarker in DLBCL needs to be investigated badly, as well as its function and molecular mechanism. To further explore, microarray analysis was performed to identify the differentially expressed lncRNAs in DLBCL tissues. To investigate the biological functions of SMAD5-AS1, we performed gain- and loss-of-function experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assays, Argonaute 2-RNA immunoprecipitation (AGO2-RIP), RNA pull-down assay, quantitative PCR arrays, western blot assay, TOPFlash/FOPFlash reporter assay, and rescue experiments were conducted to explore the underlying mechanisms of competitive endogenous RNAs (ceRNAs). We found that SMAD5-AS1 was down-regulated in DLBCL tissues and cell lines. Functionally, SMAD5-AS1 downregulation promoted cell proliferation in vitro and in vivo, whereas SMAD5-AS1 overexpression could lead to the opposite effects in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-135b-5p was a direct target of SMAD5-AS1, which was validated by dual-luciferase reporter assays, AGO2-RIP, RNA pull-down assay, and rescue experiments. Also, dual-luciferase reporter assays and rescue experiments demonstrated that miR-135b-5p targeted the adenomatous polyposis coli (APC) gene directly. SMAD5-AS1/miR-135b-5p inhibits the cell proliferation via inactivating the classic Wnt/β-catenin pathway in the form of APC dependency. Our results indicated that SMAD5-AS1 inhibits DLBCL proliferation by sponging miR-135b-5p to up-regulate APC expression and inactivate classic Wnt/β-catenin pathway, suggesting that SMAD5-AS1 may act as a potential biomarker and therapeutic target for DLBCL.

Circulating CCR2 + monocytes are crucial for maintaining the adult tissue-resident F4/80 hi MHCII hi macrophage pool in the intestinal lamina propria. Here we show that a subpopulation of CCR2-independent F4/80 hi MHCII low macrophages, which are the most abundant F4/80 hi cells in neonates, gradually decline in number in adulthood; these macrophages likely represent the fetal contribution to F4/80 hi cells. In colon adenomas of Apc Min/+ mice, F4/80 hi MHCII low macrophages are not only preserved, but become the dominant subpopulation among tumour-resident macrophages during tumour progression. Furthermore, these pro-tumoural F4/80 hi MHCII low and F4/80 hi MHCII hi macrophages can self-renew in the tumour and maintain their numbers mostly independent from bone marrow contribution. Analyses of colon adenomas indicate that CSF1 may be a key facilitator of macrophage self-renewal. In summary, the tumour microenvironment creates an isolated niche for tissue-resident macrophages that favours macrophage survival and self-renewal. Tissue-resident F4/80 hi macrophages can be found both in normal gut as well as in intestinal tumours. Here the authors show that in the colon these macrophages are CCR2-dependent, while in tumours they gain the ability to self-renew, relying on CSF1 and promoting cancer progression.

ABSTRACT Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APC Min/+ mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy.