One of the most important mechanisms by which cancer fosters its own development is the generation of an immune microenvironment that inhibits or impairs antitumor immune responses. A cancer permissive immune microenvironment is present in a large proportion of the patients with cancer who do not respond to immunotherapy approaches intended to trigger preexisting antitumor immune responses, for instance, immune checkpoint blockade. High circulating levels of IL8 in patients with cancer quite accurately predict those who will not benefit from checkpoint-based immunotherapy. IL8 has been reported to favor cancer progression and metastases via different mechanisms, including proangiogenesis and the maintenance of cancer stem cells, but its ability to attract and functionally modulate neutrophils and macrophages is arguably one of the most important factors. IL8 does not only recruit neutrophils to tumor lesions, but also triggers the extrusion of neutrophil extracellular traps (NET). The relevance and mechanisms underlying the contribution of both neutrophils and NETs to cancer development and progression are starting to be uncovered and include both direct effects on cancer cells and changes in the tumor microenvironment, such as facilitating metastasis, awakening micrometastases from dormancy, and facilitating escape from cytotoxic immune cells. Blockade of IL8 or its receptors (CXCR1 and CXCR2) is being pursued in drug development, and clinical trials alone or in combination with anti-PD-L1 checkpoint inhibitors are already ongoing.

IL8, Neutrophils, and NETs in a Collusion against Cancer Immunity and Immunotherapy.

At the frontline of the host defense response, neutrophil antimicrobial functions have adapted to combat infections and injuries of different origins and magnitude. The release of web-like DNA structures named neutrophil extracellular traps (NETs) constitutes an important mechanism by which neutrophils prevent pathogen dissemination or deal with microorganisms of a bigger size. At the same time, nuclear and granule proteins with microbicidal activity bind to these DNA structures promoting the elimination of entrapped pathogens. However, these toxic properties may produce unwanted effects in the host, when neutrophils uncontrollably release NETs upon persistent inflammation. As a consequence, NET accumulation can produce vessel occlusion, tissue damage, and prolonged inflammation associating with the progression and exacerbation of multiple pathologic conditions. This review outlines recent advances in understanding the mechanisms of NET release and functions in sterile disease. We also discuss mechanisms of physiological regulation and the importance of neutrophil heterogeneity in NET formation and composition.

Neutrophil extracellular traps: from physiology to pathology.

Neutrophil extracellular traps in cancer

Neutrophil extracellular traps (NET) are the extracellular release of decondensed chromatin and granules known for their role in host defense against foreign pathogens. However, a novel and predominantly pro-tumorigenic role of NETs in cancer is emerging. Tumors induce NET formation through the secretion of an array of tumor and infection-derived factors. NET deposition favors tumor cell proliferation, immunosuppression and cancer-associated thrombosis. Moreover, NETs enhance metastasis by contributing to epithelial-to-mesenchymal transition. A mesenchymal transition in tumor cells potentiates their migratory and invasive abilities. Circulating NETs capture circulating tumor cells and increase vascular permeability, thereby promoting tumor cell intravasation and establishment of micrometastasis. NETs present in pre-metastatic niches serve as cytokines in the recruitment of tumor cells through CCDC25. Through NET-mediated laminin remodelling, dormant cells are reawakened favoring metastatic growth. Moreover, post-operative infection results in high NET deposition and exacerbates post-surgical cancer progression and recurrence. Anti-NET therapies are in use for autoimmune diseases and are now being investigated in the context of cancer. The hope is that anti-NET therapies may synergize with existing anti-cancer therapy to increase rate of response given their multi-faceted interplay in several domains of cancer progression.

The role of neutrophil extracellular traps in cancer progression and metastasis.

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8.

Neutrophils are a significant population of infiltrated immune cells in the tumor microenvironment Neutrophil extracellular traps (NETs) are implicated in the biological behavior of many malignant tumors NETs can be degraded into soluble nucleosomes, leading to the release of fragments containing DNA and granule proteins into the peripheral blood (PB) Using human gastric cancer (GC) biopsies and PB samples, we investigated the specific value of NETs in GC from a clinical perspective In summary, the formation of NETs was discovered in the tissue microenvironment and PB of GC patients The amounts of NETs and neutrophil accumulation decreased from tumor tissue to paratumor tissue In addition, the level of NETs in the PB gradually declined through the following patient populations: advanced disease patients, preoperative patients, postoperative patients, benign disease patients, and healthy controls The levels of NETs in the plasma and serum were significantly correlated As a serum biomarker, NETs had a better diagnostic value than carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in GC The neutrophil count and neutrophil to lymphocyte ratio (NLR) were significantly associated with the level of NETs in the PB The existence of lymph node metastasis indicated a high level of NETs in the serum Moreover, the level of NETs in the PB was inversely correlated with short-term efficacy in GC patients who had received advanced first-line treatment The higher baseline level of NETs in the PB of patients with negative HER2 status was correlated with worse progression-free survival (PFS) And the level of NETs in the PB was a unfavorable independent prognostic factor for PFS in patients with advanced GC who had received first-line treatment Thus, NETs have novel diagnostic, therapeutic predictive, and prognostic value in GC patients

/pdf/diagnostic-therapeutic-predictive-and-prognostic-value-of-2fnk3x69bw.pdf

Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma.

Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 ( P  = 0.010) and positive cell infiltration of MPO ( P  = 0.004) in tumor tissues as well as positive expression of BRCA1 ( P P  = 0.021), BRCA2 ( P P  = 0.039) were independent prognostic factors for disease-free survival. BRCA1 ( P  = 0.005) and BRCA2 ( P P

Prognostic Value of the Expression of DNA Repair-Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients.

Excision repair cross-complementing gene-1 (ERCC1) is a key regulatory enzyme whose expression patterns in tumor tissues are associated with survival in gastric cancer. The present study aimed to evaluate the effects of ERCC1 expression in peripheral blood lymphocytes (PBLs) on the outcome of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy. Tumor and PBL samples from 48 patients treated with adjuvant oxaliplatin-based chemotherapy for gastric cancer were analyzed. Immunohistochemistry was used to assess the expression of ERCC1. After a median follow-up of 18.5 months, the median disease-free survival (DFS) and overall survival (OS) were 12 and 20 months, respectively. Expression of ERCC1 was found in 72.9% (35/48), 56.3% (27/48), and 10.0% (2/20) of tumor tissues, PBLs from gastric cancer patients, and PBLs from controls, respectively. A significant positive correlation between ERCC1 expression in PBL and cancer tissue was found (χ(2) = 12.098, P = 0.001, Pearson contingency coefficient = 0.502). Patients with negative expression of ERCC1 in tumor tissues had a significantly longer median DFS and median OS compared to patients with positive expression of ERCC1 (median DFS, 18 vs 10 months, P = 0.006; median OS, 30 vs 17 months, P = 0.012). In PBLs, high expression of ERCC1 was associated with decreased DFS (9 vs 18 months, P = 0.032), but not OS (16 vs 24 months, P = 0.057). Patients with gastric cancer exhibiting negative expression of ERCC1 are more likely to benefit from oxaliplatin-based adjuvant chemotherapy.

/pdf/correlation-of-ercc1-expression-in-peripheral-blood-202apaaksf.pdf

Correlation of ERCC1 expression in peripheral blood lymphocytes with outcomes of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy.

Introduction. Growing evidence indicates that Rictor (Rapamycin-insensitive companion of mTOR) is overexpressed across several malignancies and associated with poor survival. However, only limited data indicate that Rictor plays a role in gastric cancer (GC). We sought to explore the prognostic value of Rictor in GC and present interaction analysis between Rictor expression and H. pylori status regarding their effects over the prognosis of GC patient. Materials and methods. 250 GC tissues and 124 lymph node metastases were collected for the detection of Rictor by immunohistochemistry. Cox regression model was used to assess the association between Rictor expression and patient prognosis. Functional experiments were examined in transfected cells using Rictor siRNA. Additive and multiplicative interactions of Rictor and H. pylori were evaluated. Results. In this study, the positive rate of Rictor was 51.6% (129/150) in GC tissues. Multivariate analyses showed that Rictor was independent unfavorable predictor for OS (HR = 1.554, 95% CI = 1.076–2.244, P = 0.019) and DFS (HR = 1.556, 95% CI = 1.081–2.240, P = 0.017). Patients with upregulated Rictor in the primary tumor and lymph node metastases had the worst prognosis. We observed significant additive and multiplicative interactions between Rictor expression and H. pylori status for OS and DFS (P < 0.05). Our in vitro experiment showed that knockdown of Rictor could suppress cell proliferation, induce apoptosis and inhibit tumor migration and invasion. Conclusion. Our results demonstrate that Rictor, acting as an oncogene, might be a potential prognostic biomarker and therapeutic target in GC. We suggest that Rictor expression and H. pylori status may be a prognostic marker in gastric cancer.

/pdf/overexpression-of-rictor-protein-and-rictor-h-pylori-13g9vxmqdc.pdf

Overexpression of Rictor protein and Rictor-H. pylori interaction has impact on tumor progression and prognosis in patients with gastric cancer.

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Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma.

Prognostic Value of the Expression of DNA Repair-Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients.

Correlation of ERCC1 expression in peripheral blood lymphocytes with outcomes of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy.

Overexpression of Rictor protein and Rictor-H. pylori interaction has impact on tumor progression and prognosis in patients with gastric cancer.