Tackling immunomonitoring in gastrointestinal cancer.

PURPOSE OF REVIEW: The growing awareness that the immune system is a key player in the antitumoral response and the excellent clinical results achieved in some settings with anti-programmed cell death 1 (PD1)/programmed death ligand 1 (PDL1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) drugs has led to the rise of immunotherapy as a supplement or an alternative to conventional cancer treatment. The high costs associated with these therapies, their significant toxicity and the need to understand and circumvent immune escape mechanisms raise the urgent need for immunological assessment of therapy response. The study of the immunological parameters before, during and after treatment is referred to as immunomonitoring. This review discusses the current knowledge of immunomonitoring markers in gastrointestinal cancers. RECENT FINDINGS: The last decade has seen a collaborative effort to standardize the assays performed in clinical trials to assess response to immunotherapy. Since then, multiple studies have been conducted on blood samples, biopsies and surgical specimens to determine their immunological profiles leading to the identification of several immunological markers possessing a predictive value of response to treatment. SUMMARY: Future research will focus on detangling the predictive value of immune markers in different therapeutic models, and also to develop new noninvasive means to monitor the immune response of patients. VIDEO ABSTRACT: http://links.lww.com/COON/A20.

Fat density is a novel prognostic marker in patients with esophageal cancer.

BACKGROUND & AIMS: While long-term obesity is a well-known risk factor for esophageal adenocarcinoma (ADC), recent weight loss represents a significant concern in esophageal cancer (EC), in relation with dysphagia and disease aggressiveness. These phenomenons may diversely impact the adipose tissue density, suggested in other cancer settings as an important prognostic biomarker. The analysis of body mass composition (BMC) parameters, including adipose tissue attenuation is studied here in a population of EC operated with curative intent. METHODS: BMC was retrospectively evaluated on Computed-Tomography (CT)-scan images from fluorodeoxyglucose (FDG)-positron-emitting (PET)/CT scans performed as a diagnostic procedure in a cohort of 145 EC patients operated with curative intent The mean subcutaneous (SFD) and visceral fat (VFD) density along with the index (area/height2) (SF index (SFI), VF index (VFI)) were assessed on two adjacent slides at the third lumbar vertebra level by two independent investigators. Overall survival (OS) was calculated from the date of the baseline FDG-PET/CT scan. RESULTS: Inter-observer correlations are excellent for all BMC parameters (r = 0.94-0.99). As expected, weight loss is associated with worse outcome. We show that low SFD (HR 0.5 (95% CI: 0.3-0.7), p < 0.001) and low VFD (HR 0.6 (95% CI: 0.4-0.9), p = 0.04) at diagnosis are associated with better OS. In contrast, body mass index (BMI) fails to show any relevance in predicting survival. CONCLUSIONS: Adipose tissue density is an important prognostic factor in EC.

Infiltrative tumour growth pattern correlates with poor outcome in oesophageal cancer.

OBJECTIVE: Oesophageal cancer (OEC) is an aggressive disease with a poor survival rate. Prognostic markers are thus urgently needed. Due to the demonstrated prognostic value of histopathological growth pattern (HGP) in other cancers, we performed a retrospective assessment of HGP in patients suffering from invasive OEC. DESIGN: A first cohort composed of 89 treatment-naïve operated patients with OEC from The Cancer Genome Atlas (TCGA) public database was constituted, from which H&E images and RNA-sequencing data were retrieved. Next, a second cohort composed of 99 patients with OEC treated and operated in a Belgian hospital was established. H&E-stained sections and extracted tumorous RNA were obtained from the samples. HGP were assessed on H&E slides as infiltrative (IGP) or expansive (EGP). TCGA RNA-sequencing data were analysed through the gene set enrichment analysis and Cytoscape softwares. Real-time quantitative PCR (qPCR) experiments were performed to assess gene expression in the Belgian cohort. RESULTS: IGP patients displayed a grim prognosis compared with EGP patients, while IGP was found as associated with numerous lymphovascular emboli and perinervous infiltrations. Analyses of the TCGA expression data showed that angiogenesis, epithelial-to-mesenchymal transition (EMT) and inflammation were significantly upregulated in IGP compared with EGP samples. qPCR experiments of three genes appearing as highly upregulated in each pathway showed no difference in expression according to the HGP. CONCLUSION: The current study demonstrates the poor prognostic value carried by IGP in OC and suggests angiogenesis, EMT and inflammation as key carcinogenetic pathways upregulated in this pattern.

The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells.

Follicular helper T cells (Tfh) have been identified as the primary cell subpopulation regulating B cell responses in germinal centers, thus supporting high-affinity antibody production. Among the transcription factors orchestrating Tfh cell differentiation and function, the role played by the proto-oncogene c-Maf remains poorly characterized. We report herein that selective loss of c-Maf expression in the T cell compartment results in defective development of Tfh cells in response to both antigen/adjuvant vaccinations and commensal intestinal bacteria. Accordingly, c-Maf expression in T cells was essential for the development and high-affinity antibody secretion in vaccinated animals. c-Maf was expressed early, concomitantly to BCL6, in Tfh cell precursors and found to regulate Tfh fate in a cell-autonomous fashion. Altogether, our findings reveal a novel, non-redundant, function for c-Maf in the differentiation of Tfh cells and the regulation of humoral immune responses to T-cell-dependent antigens.

Antigen-presenting cell-derived IL-6 restricts the expression of GATA3 and IL-4 by follicular helper T cells.

Follicular helper T cells (Tfh) support high-affinity Ab production by germinal center B cells through both membrane interactions and secretion of IL-4 and -21, two major cytokines implicated in B-cell survival and Ab class switch. Tfh-2 cells recently emerged in humans as a strong IL-4 producer Tfh cell subset implicated in both autoimmune and allergic diseases. Although the molecular mechanisms governing Tfh cell differentiation from naive T cells have been widely described, much less is known about the regulation of cytokine secretion by mouse Tfh-2 cells. The purpose of our study was to evaluate the role of dendritic cell-derived IL-6 in fine-tuning cytokine secretion by Tfh cells. Our results demonstrate that priming of Th cells by IL-6-deficient antigen-presenting dendritic cells preferentially leads to accumulation of a subset of Tfh cells characterized by high expression of GATA3 and IL-4, associated with reduced production of IL-21. STAT3-deficient Tfh cells also overexpress GATA3, suggesting that early IL-6/STAT3 signaling during Tfh cell development inhibits the expression of a set of genes associated with the Th2 differentiation program. Overall, our data indicate that IL-6/STAT3 signaling restrains the expression of Th2-like genes in Tfh cells, thus contributing to the control of IgE secretion in vivo.