Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells.

Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-ß-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-ß-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

CAR-NK cells for gastrointestinal cancer immunotherapy: from bench to bedside.

BACKGROUND: Gastrointestinal (GI) cancers represent a significant health burden worldwide. Their incidence continues to increase, and their management remains a clinical challenge. Chimeric antigen receptor (CAR) natural killer (NK) cells have emerged as a promising alternative to CAR-T cells for immunotherapy of GI cancers. Notably, CAR-NK cells offer several advantages, including reduced risk of graft-versus-host disease, lower cytokine release syndrome, and the ability to target cancer cells through both CAR-dependent and natural cytotoxic mechanisms. MAIN BODY: This review comprehensively discusses the development and applications of CAR-NK cells in the treatment of GI cancers. We explored various sources of NK cells, CAR design strategies, and the current state of CAR-NK cell therapy for GI cancers, highlighting recent preclinical and clinical trials. Additionally, we addressed existing challenges and propose potential strategies to enhance the efficacy and safety of CAR-NK cell therapy. CONCLUSIONS: Our findings highlight the potential of CAR-NK cells to revolutionize GI cancer treatment and pave the way for future clinical applications.

Machine learning for the identification of neoantigen-reactive CD8 + T cells in gastrointestinal cancer using single-cell sequencing.

BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.

Prognostic and predictive factors in advanced upper gastrointestinal cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis of the current evidence.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for upper gastrointestinal cancers (UGICs). However, durable clinical responses only existed in a minority of patients. We evaluated evidence predicting survival benefits to identify the optimal population followed by ICI-based therapy. METHODS: A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science to identify clinical trials for UGICs with ICI-based therapy. The outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation System (GRADE). RESULTS: Thirty-six studies comprising 12,440 patients were included for quantitative synthesis. Patients with PD-L1-positive (OR = 2.08, p < 0.00001), EBV+ (OR = 8.47, p = 0.003) tumors were more likely to respond to ICI treatment. Moreover, OS was significantly improved with the statistical subgroup difference concerning sex (p = 0.02) and region (p = 0.02). An exploratory subgroup analysis showed significantly improved OS with ICI plus chemotherapy in patients with CPS ≥ 10 (HR = 0.66, p = 0.001) and CPS ≥ 1 (HR = 0.75, p < 0.00001). CONCLUSION: UGIC patients with PD-L1-positive, EBV + status are associated with a better therapeutic response to ICI-based therapy. The male patients and Asian patients could derive more survival benefits following ICI treatment than female and non-Asian ones. A combination of prognostic and predictive factors was suggested to help guide immunotherapy decision-making in UGIC patients.

Association of the Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) score with immune checkpoint inhibitor efficacy in patients with gastrointestinal and lung cancer.

OBJECTIVE: This study aimed to conduct a comprehensive analysis, evaluating the prognostic significance of the baseline Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) Score in patients undergoing immune checkpoint inhibitor (ICI) therapy. METHODS: A comprehensive search was performed across various databases, including PubMed, the Cochrane Library, EMBASE, and Google Scholar, until October 21, 2023, to compile relevant articles for analysis. The investigation encompassed diverse clinical outcomes, including overall survival (OS) and progression-free survival (PFS). RESULTS: This analysis included a total of 15 articles, comprising 19 studies involving 3335 patients. Among the 19 studies, nine studies focused on NSCLC, and six studies were conducted on HCC. Pooled results revealed that patients with elevated ALI levels experienced prolonged OS (HR: 0.51, 95% CI: 0.37-0.70, p < 0.001) and extended PFS (HR: 0.61, 95% CI: 0.52-0.72, p < 0.001). Furthermore, a GRIm score > 1 was associated with reduced OS (HR: 2.07, 95% CI: 1.47-2.92, p < 0.001) and diminished PFS (HR: 1.78, 95% CI: 1.35-2.34, p < 0.001) in cancer patients receiving ICIs. Subgroup analysis indicated that ALI cutoff values of 18 exhibited enhanced predictive potential. Additionally, for HCC patients, those with HCC-GRIm score > 2 showed a substantially decreased risk of mortality compared to individuals with HCC-GRIm score ≤ 2 (HR: 2.63, 95% CI: 1.89-3.65, p < 0.001). CONCLUSION: The ALI and GRIm score served as dependable prognostic indicators for patients undergoing ICI therapy in the context of cancer treatment.

The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

A prognostic model established using bile acid genes to predict the immunity and survival of patients with gastrointestinal cancer.

BACKGROUND: The metabolism of abnormal bile acids (BAs) is implicated in the initiation and development of gastrointestinal (GI) cancer. However, there was a lack of research on the molecular mechanisms of BAs metabolism in GI. METHODS: Genes involved in BAs metabolism were excavated from public databases of The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, and Molecular Signatures Database (MSigDB). ConsensusClusterPlus was used to classify molecular subtypes for GI. To develop a RiskScore model for predicting GI prognosis, univariate Cox analysis was performed on the genes in protein-protein interaction (PPI) network, followed by using Lasso regression and stepwise regression to refine the model and to determine the key prognostic genes. Tumor immune microenvironment in GI patients from different risk groups was assessed using the ESTIMATE algorithm and enrichment analysis. Reverse transcription-quantitative real-time PCR (RT-qPCR), Transwell assay, and wound healing assay were carried out to validate the expression and functions of the model genes. RESULTS: This study defined three molecular subtypes (C1, C2, and C3). Specifically, C1 had the best prognosis, while C3 had the worst prognosis with high immune checkpoint gene expression levels and TIDE scores. We selected nine key genes (AXIN2, ATOH1, CHST13, PNMA2, GYG2, MAGEA3, SNCG, HEYL, and RASSF10) that significantly affected the prognosis of GI and used them to develop a RiskScore model accordingly. Combining the verification results from a nomogram, the prediction of the model was proven to be accurate. The high RiskScore group was significantly enriched in tumor and immune-related pathways. Compared with normal gastric mucosal epithelial cells, the mRNA levels of the nine genes were differential in the gastric cancer cells. Inhibition of PNMA2 suppressed migration and invasion of the cancer cells. CONCLUSION: We distinguished three GI molecular subtypes with different prognosis based on the genes related to BAs metabolism and developed a RiskScore model, contributing to the diagnosis and treatment of patients with GI.

A Narrative Review: Immunometabolic Interactions of Host-Gut Microbiota and Botanical Active Ingredients in Gastrointestinal Cancers.

The gastrointestinal tract is where the majority of gut microbiota settles; therefore, the composition of the gut microbiota and the changes in metabolites, as well as their modulatory effects on the immune system, have a very important impact on the development of gastrointestinal diseases. The purpose of this article was to review the role of the gut microbiota in the host environment and immunometabolic system and to summarize the beneficial effects of botanical active ingredients on gastrointestinal cancer, so as to provide prospective insights for the prevention and treatment of gastrointestinal diseases. A literature search was performed on the PubMed database with the keywords "gastrointestinal cancer", "gut microbiota", "immunometabolism", "SCFAs", "bile acids", "polyamines", "tryptophan", "bacteriocins", "immune cells", "energy metabolism", "polyphenols", "polysaccharides", "alkaloids", and "triterpenes". The changes in the composition of the gut microbiota influenced gastrointestinal disorders, whereas their metabolites, such as SCFAs, bacteriocins, and botanical metabolites, could impede gastrointestinal cancers and polyamine-, tryptophan-, and bile acid-induced carcinogenic mechanisms. GPRCs, HDACs, FXRs, and AHRs were important receptor signals for the gut microbial metabolites in influencing the development of gastrointestinal cancer. Botanical active ingredients exerted positive effects on gastrointestinal cancer by influencing the composition of gut microbes and modulating immune metabolism. Gastrointestinal cancer could be ameliorated by altering the gut microbial environment, administering botanical active ingredients for treatment, and stimulating or blocking the immune metabolism signaling molecules. Despite extensive and growing research on the microbiota, it appeared to represent more of an indicator of the gut health status associated with adequate fiber intake than an autonomous causative factor in the prevention of gastrointestinal diseases. This study detailed the pathogenesis of gastrointestinal cancers and the botanical active ingredients used for their treatment in the hope of providing inspiration for research into simpler, safer, and more effective treatment pathways or therapeutic agents in the field.

[Real-World Data of Immunohistochemical Staining for DNA Mismatch Repair Proteins Highlight Candidates for Immune Checkpoint Inhibitor Treatment in Patients with Gastrointestinal Cancer].

Overall assessment of KEYNOTE-164 study, KEYNOTE-158 study and CheckMate 142 study demonstrated the clinical benefits of immune checkpoint inhibitors(ICIs)among patients with mismatch repair deficient(dMMR)/high microsatellite instability(MSI-H)cancer. As a result, ICIs have been approved for treatment of MSI-H solid tumor regardless of the tumor type. However, the frequency of real-world diagnosed dMMR gastrointestinal cancer were rarely reported. Therefore, the results of immunohistochemical staining for DNA mismatch repair proteins was investigated. 175 samples of gastrointestinal cancers were examined between November 2019 and June 2023. Clinical and pathological characteristics were obtained from clinical and histopathological records. In real world populations with high proportion of elderly people, the frequency of diagnosed dMMR gastrointestinal cancer may be high compared with previous reports. Furthermore, based on the deficient pattern of mismatch repair protein and age, most cases classified as dMMR may be sporadic. Right side tumors and female may increase the likelihood of dMMR colorectal cancer. The current results justified immunohistochemical staining for DNA mismatch repair proteins, strongly involved in the appropriate patient selection for ICIs therapy, should be conducted for elderly patients newly diagnosed as gastrointestinal cancer. We believe that further clinical cancer immunology research, and then challenging insight targeting dMMR gastrointestinal cancer will result in future development of novel immunotherapy combination strategies well tolerated even in elderly patients.

Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer.

Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion.

The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies.

Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to ß-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers.

Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole-genome and matched RNA-sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense-mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein-Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1 Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers.

Human splenic myeloid derived suppressor cells: Phenotypic and clustering analysis.

Myeloid derived suppressor cells (MDSCs) can be subset into monocytic (M-), granulocytic (G-) or polymorphonuclear (PMN-), and immature (i-) or early MDSCs and have a role in many disease states. In cancer patients, the frequencies of MDSCs can positively correlate with stage, grade, and survival. Most clinical studies into MDSCs have been undertaken with peripheral blood (PB); however, in the present studies, we uniquely examined MDSCs in the spleens and PB from patients with gastrointestinal cancers. In our studies, MDSCs were rigorously subset using the following markers: Lineage (LIN) (CD3, CD19 and CD56), human leukocyte antigen (HLA)-DR, CD11b, CD14, CD15, CD33, CD34, CD45, and CD16. We observed a significantly higher frequency of PMN- and M-MDSCs in the PB of cancer patients as compared to their spleens. Expression of the T-cell suppressive enzymes arginase (ARG1) and inducible nitric oxide synthase (i-NOS) were higher on all MDSC subsets for both cancer patients PB and spleen cells as compared to MDSCs from the PB of normal donors. Similar findings for the activation markers lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), program death ligand 1 (PD-L1) and program cell death protein 1 (PD-1) were observed. Interestingly, the total MDSC cell number exported to clustering analyses was similar between all sample types; however, clustering analyses of these MDSCs, using these markers, uniquely documented novel subsets of PMN-, M- and i-MDSCs. In summary, we report a comparison of splenic MDSC frequency, subtypes, and functionality in cancer patients to their PB by clustering and cytometric analyses.

ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors.

BACKGROUND: Integrin Subunit Alpha 5 (ITGA5), belongs to the integrin alpha chain family, is vital for promoting cancer cell invasion, metastasis. However, the correlation between ITGA5 expression and immune infiltration in gastrointestinal tumors remain unclear. METHODS: The expression level of ITGA5 was detected by Oncomine and Tumor Immune Estimation Resource (TIMER). The association between ITGA5 and prognosis of patients was identified by Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and PrognoScan. We evaluated the correlation between ITGA5 expression and immune infiltrating level via TIMER. Besides, TIMER, immunohistochemistry (IHC) staining and western blot were used to explore correlations between ITGA5 expression and markers of immune infiltrates cells. Furthermore, we constructed protein-protein interaction (PPI) network and performed functional enrichment by GeneMANIA and Metascape. RESULTS: ITGA5 was generally overexpressed and correlated with worse prognosis in multiple types of gastrointestinal tumors. In addition, ITGA5 expression level was significantly associated with tumor purity and immune infiltration levels of different immune cells in gastrointestinal tumors. Interestingly, immune markers for monocytes, tumor - associated macrophages (TAMs), macrophages 2 (M2) cells and T-helper 2 (Th2) cells were found to be significantly and positively correlated with ITGA5 expression levels in colon and gastric cancer. Results from IHC staining and western blot further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels. Lastly, interaction network and function enrichment analysis revealed ITGA5 was mainly involved in "integrin mediated signaling pathway", "leukocyte migration", "cell-substrate adhesion". CONCLUTIONS: Our study demonstrated that ITGA5 may act as an essential regulator of tumor immune cell infiltration and a valuable prognostic biomarker in gastrointestinal tumors. Additional work is needed to fully elucidate the underlying mechanisms behind these observations.

Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival.

BACKGROUND: Atypical tumor response patterns during immune checkpoint inhibitor therapy pose a challenge to clinicians and investigators in immuno-oncology practice. This study evaluated tumor burden dynamics to identify imaging biomarkers for treatment response and overall survival (OS) in advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors. METHODS: This retrospective study enrolled a total of 198 target lesions in 75 patients with advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors between January 2017 and March 2021. Tumor diameter changes as defined by immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) were studied to determine treatment response and association with OS. RESULTS: Based on the best overall response, the tumor diameter ranged from - 100 to + 135.3% (median: - 9.6%). The overall response rate was 32.0% (24/75), and the rate of durable disease control for at least 6 months was 30.7% (23/75, one (iCR, immune complete response) or 20 iPR (immune partial response), or 2iSD (immune stable disease). Using univariate analysis, patients with a tumor diameter maintaining a < 20% increase (48/75, 64.0%) from baseline had longer OS than those with ≥20% increase (27/75, 36.0%) and, a reduced risk of death (median OS: 80 months vs. 48 months, HR = 0.22, P = 0.034). The differences in age (HR = 1.09, P = 0.01), combined surgery (HR = 0.15, P = 0.01) and cancer type (HR = 0.23, P = 0.001) were significant. In multivariable analysis, patients with a tumor diameter with a < 20% increase had notably reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, mismatch repair (MMR) status, treatment course and cancer differentiation. Two patients (2.7%) showed pseudoprogression. CONCLUSIONS: Tumor diameter with a < 20% increase from baseline during therapy in gastrointestinal malignancies was associated with therapeutic benefit and longer OS and may serve as a practical imaging marker for treatment response, clinical outcome and treatment decision making.

Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study.

INTRODUCTION: Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. METHODS: We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. RESULTS: In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. DISCUSSION: The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.

Prospects and Challenges of the Study of Anti-Glycan Antibodies and Microbiota for the Monitoring of Gastrointestinal Cancer.

Over the past decades, a large amount of data has been accumulated in various subfields of glycobiology. However, much clinically relevant data and many tools are still not widely used in medicine. Synthetic glycoconjugates with the known structure of glycans are an accurate tool for the study of glycan-binding proteins. We used polyacrylamide glycoconjugates (PGs) including PGs with tumour-associated glycans (TAGs) in immunoassays to assess the prognostic potential of the serum level of anti-glycan antibodies (AG Abs) in gastrointestinal cancer patients and found an association of AG Abs with survival. The specificity of affinity-isolated AG Abs was investigated using synthetic and natural glycoconjugates. AG Abs showed mainly a low specificity to tumour-associated and tumour-derived mucins; therefore, the protective role of the examined circulating AG Abs against cancer remains a challenge. In this review, our findings are analysed and discussed in the context of the contribution of bacteria to the AG Abs stimulus and cancer progression. Examples of the influence of pathogenic bacteria colonising tumours on cancer progression and patient survival through mechanisms of interaction with tumours and dysregulated immune response are considered. The possibilities and problems of the integrative study of AG Abs and the microbiome using high-performance technologies are discussed.

Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging.

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.

Dissecting Response to Cancer Immunotherapy by Applying Bayesian Network Analysis to Flow Cytometry Data.

Cancer immunotherapy, specifically immune checkpoint blockade, has been found to be effective in the treatment of metastatic cancers. However, only a subset of patients achieve clinical responses. Elucidating pretreatment biomarkers predictive of sustained clinical response is a major research priority. Another research priority is evaluating changes in the immune system before and after treatment in responders vs. nonresponders. Our group has been studying immune networks as an accurate reflection of the global immune state. Flow cytometry (FACS, fluorescence-activated cell sorting) data characterizing immune cell panels in peripheral blood mononuclear cells (PBMC) from gastroesophageal adenocarcinoma (GEA) patients were used to analyze changes in immune networks in this setting. Here, we describe a novel computational pipeline to perform secondary analyses of FACS data using systems biology/machine learning techniques and concepts. The pipeline is centered around comparative Bayesian network analyses of immune networks and is capable of detecting strong signals that conventional methods (such as FlowJo manual gating) might miss. Future studies are planned to validate and follow up the immune biomarkers (and combinations/interactions thereof) associated with clinical responses identified with this computational pipeline.