Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts

A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

Design of Optimal Deep Learning-Based Pancreatic Tumor and Nontumor Classification Model Using Computed Tomography Scans

Pancreatic tumor is a lethal kind of tumor and its prediction is really poor in the current scenario. Automated pancreatic tumor classification using computer-aided diagnosis (CAD) model is necessary to track, predict, and classify the existence of pancreatic tumors. Artificial intelligence (AI) can offer extensive diagnostic expertise and accurate interventional image interpretation. With this motivation, this study designs an optimal deep learning based pancreatic tumor and nontumor classification (ODL-PTNTC) model using CT images. The goal of the ODL-PTNTC technique is to detect and classify the existence of pancreatic tumors and nontumor. The proposed ODL-PTNTC technique includes adaptive window filtering (AWF) technique to remove noise existing in it. In addition, sailfish optimizer based Kapur’s Thresholding (SFO-KT) technique is employed for image segmentation process. Moreover, feature extraction using Capsule Network (CapsNet) is derived to generate a set of feature vectors. Furthermore, Political Optimizer (PO) with Cascade Forward Neural Network (CFNN) is employed for classification purposes. In order to validate the enhanced performance of the ODL-PTNTC technique, a series of simulations take place and the results are investigated under several aspects. A comprehensive comparative results analysis stated the promising performance of the ODL-PTNTC technique over the recent approaches.

Toripalimab: the First Domestic Anti-Tumor PD-1 Antibody in China

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.

IGF-1 Conjugated Sub-5 nm Ultrafine Iron Oxide Nanoparticle Enhances Targeted Drug Delivery and Efficacy of DNA Topoisomerase Inhibitor SN38 for Pancreatic Cancer: An in Vitro Study

Background Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery. Methods An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of chemotherapy drug irinotecan for treating pancreatic cancer in clinic. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer and stromal cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The cancer cell targeting and induced apoptosis by developed nano-formulationIGF1-uIONP/SN38 were also investigated. Results IGF1-uIONP/SN38 demonstrated stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and <7% release for 24 hours. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 hours. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity to MiaPaCa-2 cells with IC50 of 11.8 ± 2.3 nM, but not to HEK293 human embryonic kidney cells. Conclusion The IGF1-uIONP significantly improved the delivery of SN38 to targeted pancreatic cancer cells, holding the potential for in vivo theranostic applications.

Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer

Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.

Role of Nrf2 in Pancreatic Cancer

Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor Erythroid 2-Related Factor 2/NFE2L2 (Nrf2) and its negative regulator Kelch-Like ECH-Associated Protein 1 (Keap1) provide substantial protection against damage induced by oxidative stress, and a growing body of evidence points to the canonical and noncanonical Nrf2 signaling pathway as a pharmacological target in the treatment of pancreatic diseases. In this review, we present updated evidence on the activation of the Nrf2 signaling pathway and its importance in pancreatic cancer. Our review covers potential modulators of canonical and noncanonical pathway modulation mechanisms that may have a positive effect on the therapeutic response. Finally, we describe some interesting recent discoveries of novel treatments related to the antioxidant system for pancreatic cancer, including natural or synthetic compounds with therapeutic properties.

Pancreatic stellate cells: the top managers of the pancreatic tumor microenvironment.

Background Stellate pancreatocytes, being cells - producers of stromal components, actively interact with cancer cells, determine the formation of a stromal barrier between the latter and thereby provide tumor chemoresistance. Objective The review is devoted to the analysis of recent data on the role of stellate pancreatocytes in the formation of the stromal microenvironment of pancreatic tumors, molecular mechanisms through which the regulation and realization of stellate cell functions is carried out. Methods Data processing was carried out by the method of complex material analysis. Results. Stellate pancreatocytes (PSC) exhibit phenotypically and functionally two states: inactive and active. PSC activation is carried out by cells of the developing tumor through a variety of molecular mediators. Activation triggers for PSC are Yes-associated protein, TGF-β1, miRNA let-7d, IL-8, MCP1, TGF-β2, IGFBP2, and others. 10 actively expressed genes were identified: TP53, SRC, IL6, JUN, ISG15, CAD, STAT1, OAS3, OAS1, VIM during co-cultivation of a cancer cell line (PCC) with PSC. PSC deactivation is associated with speckle-type mediator POZ (SPOP) acting through nuclear factor-kappaB, transretinoic acid (ATRA). Exhibiting their activity, PSCs express several stem cell markers, α-SMA (α-actin of smooth muscle cells), vimentin, α ITGA 11 (collagen type I receptor), α5 integrin receptor ITGA5 (fibronectin receptor), hyaluronic acid, hyaluronan synthase 2 (HAS2), hyaluronidase 1 (HYAL1), BAG3 , matrix metallopeptidase 2 (MMP2), Nodal protein, miR-1246 and miR-1290, miR-210, CCN2 (connective tissue growth factor), TRPV1, SP and CGRP (Calcitonin gene-related peptide) and many other factors. Сonclusion. Stellate pancreatocytes, being producers of the interacinar stroma, are activated by various factors (TNF-α, IL-6, MCP-1, ATP, and HMGB1, etc.), including factors produced by tumor cells of the pancreas, and act as regulators of proliferation, migration, and suppression apoptosis of the latter. An increase in the expression of α ITGA 11 (type I collagen receptor), α5 integrin receptor ITGA5 (fibronectin receptor), metallopeptidases, Nodal protein, miR-1246, miR-1290, and miR-210 is observed in tumor tissue, that indicates the activation of these cells. The maintenance of the active state of PSC is provided by tumor cells, for which stellate pancreatocytes are partners in the progression of the neoplastic process. Further study of the mechanisms of interaction in the PSC-tumor cell system creates the prospect of revealing levers of influence on the pathogenesis of pancreatic tumors.

Curative treatment of pancreatic functioning insulinoma with stereotactic ablative radiation therapy: case report

Insulinoma is the most common pancreatic neuroendocrine tumor (NET). It is a rare disease account for 1-2% of pancreatic tumors and affect approximately up to 3 patients per million per year. complete surgical resection or debulking are standard of care option. However, surgery is associated with short and long-term post-operative morbidity and may not be appropriate for all patients. In This case we present management and cure of a case of functioning insulinoma with stereotactic ablative radiosurgery in an unfit patient for surgery.