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Background: Tumor-associated macrophages (TAMs) are associated with unfavorable patient prognosis in many cancer types. However, TAMs are a heterogeneous cell population and subsets have been shown to activate tumor-infiltrating T cells and confer a good patient prognosis. Data on the prognostic value of TAMs in colorectal cancer are conflicting. We investigated the prognostic effect of TAMs in relation to tumor-infiltrating T cells in colorectal cancers. Methods: The TAM markers CD68 and CD163 were analyzed by multiplex fluorescence immunohistochemistry and digital image analysis on tissue microarrays of 1720 primary colorectal cancers. TAM density in the tumor stroma was scored in relation to T cell density (stromal CD3+ and epithelial CD8+ cells) and analyzed in Cox proportional hazards models of 5-year relapse-free survival. Multivariable survival models included clinicopathological factors, MSI status and BRAFV600E mutation status. Results: High TAM density was associated with a favorable 5-year relapse-free survival in a multivariable model of patients with stage I–III tumors (p = 0.004, hazard ratio 0.94, 95% confidence interval 0.90–0.98). However, the prognostic effect was dependent on tumoral T-cell density. High TAM density was associated with a good prognosis in patients who also had high T-cell levels in their tumors, while high TAM density was associated with poorer prognosis in patients with low T-cell levels (pinteraction = 0.0006). This prognostic heterogeneity was found for microsatellite stable tumors separately. Conclusions: This study supported a phenotypic heterogeneity of TAMs in colorectal cancer, and showed that combined tumor immunophenotyping of multiple immune cell types improved the prediction of patient prognosis. [ABSTRACT FROM AUTHOR]

Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptomic resource that can inform the immune landscape of the small intestine during Celiac disease. Celiac disease is linked to responsiveness to dietary gluten, which manifests itself as immune cell activation and the immunopathology including destruction of the epithelium of the small intestine. Here the authors apply single cell transcriptomics to characterise the immune cell compartment of the human small intestine during active Celiac disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES:In celiac disease (CD), gluten induces both adaptive and innate immune responses. Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. The aim of our study was to explore and compare the early mucosal immunological events in CD and NCGS.METHODS:We challenged 30 HLA-DQ2+ NCGS and 15 CD patients, all on a gluten-free diet, with four slices of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were collected before and after challenge. The specimens were examined for cytokine mRNA by quantitative reverse transcriptase-PCR and for MxA-expression and CD3+ intraepithelial lymphocytes (IELs) by immunohistochemistry and compared with specimens from untreated CD patients and disease controls.RESULTS:In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002) mRNA increased after in vivo gluten challenge. The interferon gamma (IFN-γ) level of treated CD patients was high both before and after challenge and did not increase significantly (P=0.06). Four IFN-γ-related genes increased significantly. Treated and untreated CD patients had comparable levels of IFN-γ. Increased expression of MxA in treated CD patients after challenge suggested that IFN-α was activated on gluten challenge. In NCGS patients only IFN-γ increased significantly (P=0.03). mRNA for heat shock protein (Hsp) 27 or Hsp70 did not change in any of the groups. Importantly, we found that the density of IELs was higher in NCGS patients compared with disease controls, independent of challenge, although lower than the level for treated CD patients.CONCLUSIONS:CD patients mounted a concomitant innate and adaptive immune response to gluten challenge. NCGS patients had increased density of intraepithelial CD3+ T cells before challenge compared with disease controls and increased IFN-γ mRNA after challenge. Our results warrant further search for the pathogenic mechanisms for NCGS. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Investigation of uncertain celiac disease (CD) in patients already on a gluten-free diet (GFD) is difficult. We evaluated HLA-DQ2-gliadin tetramers for detection of gluten-specific T cells in peripheral blood and histological changes in the duodenum after a short gluten challenge as a diagnostic tool.METHODS:HLA-DQ2+ individuals on a GFD for at least 4 weeks were investigated; 35 with uncertain diagnosis, 13 CD patients, and 2 disease controls. All participants had a challenge with four slices of gluten-containing white bread, daily for 3 days (d1-d3). An esophagogastroduodenoscopy with biopsy sampling was done on d0 and d4. Biopsies were scored according to revised Marsh criteria. Peripheral blood CD4+ T cells were isolated, stained with HLA-DQ2-gliadin peptide tetramers, and analyzed by flow cytometry on d0 and d6.RESULTS:After challenge, a positive tetramer test was seen in 11/13 CD patients. Four of these subjects also showed typical histological changes on challenge. Of the 35 patients with uncertain diagnosis, 3 were diagnosed with CD. Two of these three patients had both positive tetramer staining and histological changes in biopsies after challenge.CONCLUSIONS:Tetramer staining for gluten-specific T cells is a sensitive method in detecting an immune response in CD patients after a short gluten challenge. The prevalence of CD in the group with self-prescribed GFD was about 10%. [ABSTRACT FROM AUTHOR]

Naturally occurring regulatory T (TR) cells suppress autoreactive T cells whereas adaptive TR cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with colorectal cancer (CRC). We have shown that adaptive TR cells express COX-2 and produce PGE2 that suppress effector T cells in a manner that is reversed by COX-inhibitors. Here we demonstrate that CRC patients have elevated levels of PGE2 in peripheral blood, and CRC tissue samples and draining lymph nodes display increased numbers of FOXP3+ TR cells. Depletion of TR cells from PBMC enhanced anti-tumor T-cell responses to peptides from carcinoembryonic antigen. Furthermore, the COX inhibitor indomethacin and the PKA type I antagonist Rp-8-Br-cAMPS significantly improved the anti-tumor immune activity. We suggest that adaptive TR cells contribute to an immunosuppressive microenvironment in CRC and inhibit effector T cells by a COX-2–PGE2-dependent mechanism and thereby facilitate tumor growth. Therapeutic strategies targeting TR cells and the PGE2–cAMP pathway may be interesting to pursue to enhance anti-tumor immune activity in CRC patients. [ABSTRACT FROM AUTHOR]

The respiratory tract has an approximate surface area of 70 m2 in adult humans, which is in virtually direct contact with the outside environment. It contains a uniquely rich vascular bed containing a large pool of marginated T cells, and harbours a layer of single-cell-thick epithelial tissue through which re-oxygenation of blood must occur uninterrupted for survival. It is therefore not surprising that the respiratory tract is never more than a short step away from disaster. We have only a partial understanding of how immunological homeostasis is maintained in these tissues, but it is becoming clear that the immune system has evolved a range of specific mechanisms to deal with the unique problems encountered in this specialized microenvironment. [ABSTRACT FROM AUTHOR]