Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.

Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.

Hematopoietic stem and progenitor cells (HSPCs) that have impaired differentiation can transform into leukemic blasts. However, the mechanism that controls differentiation remains elusive. Here, we show that the genetic elimination of Proteinase 3 (PRTN3) in mice led to spontaneous myeloid differentiation. Mechanistically, our findings indicate that PRTN3 interacts with the N-terminal of STAT3, serving as a negative regulator of STAT3-dependent myeloid differentiation. Specifically, PRTN3 promotes STAT3 ubiquitination and degradation, while simultaneously reducing STAT3 phosphorylation and nuclear translocation during G-CSF-stimulated myeloid differentiation. Strikingly, pharmacological inhibition of STAT3 (Stattic) partially counteracted the effects of PRTN3 deficiency on myeloid differentiation. Moreover, the deficiency of PRTN3 in primary AML blasts promotes the differentiation of those cells into functional neutrophils capable of chemotaxis and phagocytosis, ultimately resulting in improved overall survival rates for recipients. These findings indicate PRTN3 exerts an inhibitory effect on STAT3-dependent myeloid differentiation and could be a promising therapeutic target for the treatment of acute myeloid leukemia.

The biological functions and clinical implications of lysophosphatidylcholine acyltransferase 1 (LPCAT1) remain unclarified in gastric cancer (GC). The aim of the current study was to explore the possible clinicopathological significance of LPCAT1 and its perspective mechanism in GC tissues.

The protein expression and mRNA levels of LPCAT1 were detected from in-house immunohistochemistry and public high-throughput RNA arrays and RNA sequencing. To have a comprehensive understanding of the clinical value of LPCAT1 in GC, all enrolled data were integrated to calculate the expression difference and standard mean difference (SMD). The biological mechanism of LPCAT1 in GC was confirmed by computational biology and in vitro experiments. Migration and invasion assays were also conducted to confirm the effect of LPCAT1 in GC.

Both protein and mRNA expression levels of LPCAT1 in GC were remarkably higher than those in noncancerous controls. Comprehensively, the SMD of LPCAT1 mRNA was 1.11 (95% CI = 0.86-1.36) in GC, and the summarized AUC was 0.85 based on 15 datasets containing 1727 cases of GC and 940 cases of non-GC controls. Moreover, LPCAT1 could accelerate the invasion and migration of GC by boosting the neutrophil degranulation pathway and disturbing the immune microenvironment.

An increased level of LPCAT1 may promote the progression of GC.

Lymph node (LN) metastasis is the earliest sign of metastatic spread and an established predictor of poor outcome in gallbladder cancer (GBC). Patients with LN positive GBC have a significantly worse survival (median survival- 7 months) than patients with LN negative disease (median survival- ~ 23 months) in spite of standard treatment which includes extended surgery followed by chemotherapy, radiotherapy and targeted therapy. This study aims at understanding the underlying molecular processes associated with LN metastasis in GBC. Here, we used iTRAQ-based quantitative proteomic analysis using tissue cohort comprising of primary tumor of LN negative GBC (n = 3), LN positive GBC (n = 4) and non-tumor controls (Gallstone disease, n = 4), to identify proteins associated with LN metastasis. A total of 58 differentially expressed proteins (DEPs) were found to be specifically associated with LN positive GBC based on the criteria of p value ≤ 0.05, fold change ≥ 2 and unique peptides ≥ 2. These include the cytoskeleton and associated proteins such as keratin, type II cytoskeletal 7 (KRT7), keratin type I cytoskeletal 19 (KRT19), vimentin (VIM), sorcin (SRI) and nuclear proteins such as nucleophosmin Isoform 1 (NPM1), heterogeneous nuclear ribonucleoproteins A2/B1 isoform X1 (HNRNPA2B1). Some of them are reported to be involved in promoting cell invasion and metastasis. Bioinformatic analysis of the deregulated proteins in LN positive GBC using STRING database identified 'neutrophil degranulation' and 'HIF1 activation' to be among the top deregulated pathways. Western blot and IHC analysis showed a significant overexpression of KRT7 and SRI in LN positive GBC in comparison to LN negative GBC. KRT7, SRI and other proteins may be further explored for their diagnostics and therapeutic applications in LN positive GBC.

Competitive endogenous RNA (ceRNA) networks are reported to play a crucial role in regulating cancer-associated genes. Identification of novel ceRNA networks in gallbladder cancer (GBC) may improve the understanding of its pathogenesis and might yield useful leads on potential therapeutic targets for GBC. For this, a literature survey was done to identify differentially expressed lncRNAs (DELs), miRNAs (DEMs), mRNAs (DEGs) and proteins (DEPs) in GBC. Ingenuity pathway analysis (IPA) using DEMs, DEGs and DEPs in GBC identified 242 experimentally observed miRNA-mRNA interactions with 183 miRNA targets, of these 9 (CDX2, MTDH, TAGLN, TOP2A, TSPAN8, EZH2, TAGLN2, LMNB1, and PTMA) were reported at both mRNA and protein levels. Pathway analysis of 183 targets revealed p53 signaling among the top pathway. Protein-protein interaction (PPI) analysis of 183 targets using the STRING database and cytoHubba plug-in of Cytoscape software revealed 5 hub molecules, of which 3 of them (TP53, CCND1 and CTNNB1) were associated with the p53 signaling pathway. Further, using Diana tools and Cytoscape software, novel lncRNA-miRNA-mRNA networks regulating the expression of TP53, CCND1, CTNNB1, CDX2, MTDH, TOP2A, TSPAN8, EZH2, TAGLN2, LMNB1, and PTMA were constructed. These regulatory networks may be experimentally validated in GBC and explored for therapeutic applications.