Long-Term Outcome After Resection of Hepatic and Pulmonary Metastases in Multivisceral Colorectal Cancer.

Background/objectives: Colorectal cancer (CRC) with hepatic (CRLM) and pulmonary metastases (CRLU) presents a significant clinical challenge, leading to poor prognosis. Surgical resection of these metastases remains controversial because of limited evidence supporting its long-term benefits. To evaluate the impact of surgical resection of both hepatic and pulmonary metastases on long-term survival in patients with multivisceral metastatic colorectal cancer, this retrospective cohort study included 192 patients with UICC stage IV CRC treated at a high-volume academic center.

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing.

T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment.

Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor.

Colorectal Cancer Organoid-Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses.

Unlabelled: In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived tumor organoids (PDTO) show enormous potential for preclinical testing; however, cultured tumor cells lose important characteristics, including the consensus molecular subtypes (CMS). To better reflect the cellular heterogeneity, we established the colorectal cancer organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAF) from 30 patients.

Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis.

Inflammasomes are intracellular protein complexes that promote an inflammatory host defense in response to pathogens and damaged or neoplastic tissues and are implicated in inflammatory disorders and therapeutic-induced toxicity. We investigated the mechanisms of activation for inflammasomes nucleated by NOD-like receptor (NLR) protiens. A screen of a small-molecule library revealed that several tyrosine kinase inhibitors (TKIs)-including those that are clinically approved (such as imatinib and crizotinib) or are in clinical trials (such as masitinib)-activated the NLRP3 inflammasome.

The Cytokine Network in Colorectal Cancer: Implications for New Treatment Strategies.

Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME).

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment.

More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features.

KMT9 Controls Stemness and Growth of Colorectal Cancer.

Colorectal cancer is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis.

Cross-presentation of dead-cell-associated antigens by DNGR-1 dendritic cells contributes to chronic allograft rejection in mice.

The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (DNGR-1)-dependent cross-presentation of dead-cell-associated antigens occurs after transplantation and contributes to CD8 T cell responses, chronic allograft rejection (CAR), and fibrosis. BALB/c or C57BL/6 hearts were heterotopically transplanted into WT, Clec9a , or Batf3 recipient C57BL/6 mice. Allografts were analyzed for cell infiltration, CD8 T cell activation, fibrogenesis, and CAR using immunohistochemistry, Western blot, qRT -PCR, and flow cytometry.

Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells.

The transcription factor TCF7L2 is indispensable for intestinal tissue homeostasis where it transmits mitogenic Wnt/β-Catenin signals in stem and progenitor cells, from which intestinal tumors arise. Yet, TCF7L2 belongs to the most frequently mutated genes in colorectal cancer (CRC), and tumor-suppressive functions of TCF7L2 were proposed. This apparent paradox warrants to clarify the role of TCF7L2 in colorectal carcinogenesis.

Tumor-infiltrating B cells producing antitumor active immunoglobulins in resected HCC prolong patient survival.

Background & Aims: The immunological microenvironment of HCC influences patient outcome, however, the role of B cells remains unclear. This study investigated effects of local B-cell infiltration in HCC cohorts on patient survival and immunological and molecular tumor microenvironment.

Results: Unsupervised gene expression analysis of full cancer transcriptomes (N=2158) revealed a highly co-regulated immunological cluster in HCC that mainly contained immunoglobulin fragments.

Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells.

: Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenvironment regarding proliferation, senescence and neovascularization.

Immune Architecture of Colorectal Lung Metastases and Implications for Patient Survival.

Background: Pulmonary metastases occur in 10-20% of patients with colorectal cancer and significantly influence long-term survival. In this study, the immunological architecture of colorectal lung in comparison to liver metastases and its impact on patient survival were examined.

Methods: Specimens of patients with colorectal lung and liver metastases were stained for HE, CD4, CD8, CD20, CD68 and CD45RO.

LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells.

IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3.

Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model.

Chronic inflammation and the development of malignancy in the GI tract.

The role of immunologic factors in the development of gastrointestinal (GI) neoplasia, made evident from the high degree of association of chronic intestinal or gastric inflammation with the development of cancer, has attracted much attention because it promises new ways of treating disease. Here we develop the idea that immunologic factors influence the appearance of GI cancer on two levels: (i) a basic and initiating level during which the epithelial cell is induced to undergo pre-cancerous molecular changes that render it prone to further cancer progression; and (ii) a secondary level that builds on this vulnerability and drives the cell into frank malignancy. This secondary level is uniquely dependent on a single epithelial cell signaling pathway centered on STAT3, and it is this pathway upon which stimulation of mucosal cytokine production and microbiota effects converge.

RORγt(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice.

Colorectal cancer (CRC) is one of the most common tumor entities. In patients with inflammatory bowel diseases, the development of colitis-associated colon cancer is considered a dangerous long-term complication. IL-17A and the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORγt-dependent CD4(+) IL17A(+) T helper (Th)17 cells in specimens of CRC, ulcerative colitis, and ulcerative colitis-associated colorectal cancer.

Tumor-infiltrating, interleukin-33-producing effector-memory CD8(+) T cells in resected hepatocellular carcinoma prolong patient survival.

Unlabelled: Interleukin-33 (IL-33), a cytokine with pleiotropic functions, is elevated in serum of patients with hepatocellular carcinoma (HCC). This study investigated the effects of local IL-33 expression in resected HCC on patient survival and on the immunological and molecular tumor microenvironment. Tissue of resected HCCs was stained for hematoxylin and eosin, Masson trichrome, alpha-smooth muscle actin, IL-33, CD8, and IL-13 and analyzed by flow cytometry.

The complement receptors CD46, CD55 and CD59 are regulated by the tumour microenvironment of head and neck cancer to facilitate escape of complement attack.

Background: Membrane-bound complement restriction proteins (mCRPs) CD46, CD55 and CD59 enable tumour cells to evade complement dependent cytotoxicity and antibody-dependent killing mechanisms. But less is known about the role of these mCRPs in head and neck cancer.

Methods: In this study we determined the expression of the mCRPs on head and neck squamous cell carcinoma (HNSCC) cell lines, on tumour tissue and TDLNs (tumour-draining lymph nodes) as well as on lymphocytes from HNSCC patients.

IL-13 orchestrates resolution of chronic intestinal inflammation via phosphorylation of glycogen synthase kinase-3β.

Spontaneous amelioration of inflammation (often accompanied by fibrosis) is a well-known, but poorly understood, outcome of many chronic inflammatory processes. We studied this phenomenon in a chronic trinitrobenzene sulfonic acid-induced colitis model, an experimental colitis in mice that we showed to ultimately undergo spontaneous resolution, despite continued trinitrobenzene sulfonic acid stimulation. Analysis of the mechanism of this resolution revealed that it was critically dependent on IL-13 activation of STAT6, followed by phosphorylation (inactivation) of glycogen synthase kinase-3β, at least in part via STAT6 induction of p38 MAPK.

IL-13 signaling via IL-13Rα2 triggers TGF-β1-dependent allograft fibrosis.

Background: Allograft fibrosis still remains a critical problem in transplantation, including heart transplantation. The IL-13/TGF-β1 interaction has previously been identified as a key pathway orchestrating fibrosis in different inflammatory immune disorders. Here we investigate if this pathway is also responsible for allograft fibrosis and if interference with the IL-13/TGF-β1 interaction prevents allograft fibrosis.

Aspirin prolongs survival and reduces the number of Foxp3+ regulatory T cells in a genetically engineered mouse model of pancreatic cancer.

Background And Aims: Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival. Since then, the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Only the addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival, coming along with a very uncomfortable rash in the patients.

Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation.

Background: Mice lacking Foxp3+ regulatory T (Treg) cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation.

Methods: Foxp3-GFP-DTR (human diphtheria toxin receptor) C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin).