Diffuse large B-cell lymphoma (DLBCL) is a common malignancy among people living with HIV. Macrophage enrichment of the tumour microenvironment (TME) is a prognostic factor in DLBCL among immunocompetent people, with some studies reporting that macrophage enrichment predicts a superior response to rituximab therapy. The macrophage phenotype is also important, with reportedly poorer outcomes with enrichment of anti-inflammatory (M2) macrophages. To date, the relationship between the type/number of tumour macrophages and outcomes in HIV-associated DLBCL (HIV-DLBCL) has been poorly explored. In this study, we assessed tumour macrophage numbers in a South African cohort of patients with DLBCL and a high HIV-seropositivity rate. Immunohistochemistry for CD68 and CD163 was performed on the diagnostic biopsies of 79 patients with DLBCL. Relevant information was documented from the clinical records, including disease stage, international-prognostic index score, HIV-related parameters, C-reactive protein, ferritin levels and immune cell numbers (monocytes, lymphocytes and neutrophils). Survival analysis was performed using Kaplan-Meier survival estimates, and the correlation between tumour macrophage numbers and a variety of immunological parameters was assessed using Spearman\'s rho. Of the 79 patients included, 87.2% were living with HIV, and rituximab therapy was used in 46.9%. Tumour macrophage numbers were not related to HIV status, but low pro-inflammatory (M1) macrophage numbers (CD68 + CD163 -) were significantly associated with poorer outcomes (HR 2.02, p = 0.03). M2 macrophage (CD68 + CD163 +) enrichment was not predictive of survival but was associated with improved response to rituximab therapy (HR 0.19; p = 0.002). Macrophage numbers were marginally correlated with ferritin levels, which showed modest performance as a peripheral blood biomarker of the TME macrophage status (AUC 0.6 at a level of 374 µg/L), and high ferritin levels were associated with a superior response to rituximab-therapy (HR 0.28, p = 0.034). Pro-inflammatory macrophages are important in tumour control in HIV-DLBCL, while M2 macrophage enrichment improves the response to rituximab therapy. Ferritin shows promise as a biomarker for identifying patients more likely to benefit from rituximab therapy.

Increasing evidence suggests that the gut microbiome plays a key role in a host of pathological conditions, including cancer. Indeed, the bidirectional communication that occurs between the gut and the brain, known as the \'gut-brain axis,\' has recently been implicated in brain tumour pathology. Here, we focus on current research that supports a gut microbiome-brain tumour link with emphasis on high-grade gliomas, the most aggressive of all brain tumours, and the impact on the glioma tumour microenvironment. We discuss the potential use of gut-brain axis signals to improve responses to current and future therapeutic approaches. We highlight that the success of novel treatment strategies may rely on patient-specific microbiome profiles, and these should be considered for personalised treatment approaches.

The tumour microenvironment is a complex ecosystem comprising tumour cells, and cancer stem cells, and support cells that facilitate cancer growth and escape from treatment. Cancer immunotherapy focuses on immunological pathways such as PD-1/PD-L1 and CTLA-4 to target cancer stem cells via immune cells. Small molecules, immune checkpoint inhibitors, are employed to impede tumour growth by targeting cellular mediators in the cell cycle and tumour microenvironment. Long non-coding RNAs (lncRNAs) affect the growth, development, motility, and differentiation of cancer cells by regulating gene expression and are therefore considered important biomarkers. Small molecules demonstrate their effects on gene expression and behaviour of cancer cells by inducing lncRNAs. This relationship between lncRNAs and small molecules is of great importance in terms of their impact on cancer and the tumour microenvironment. The evaluation of this communication in clinical trials is of critical importance for the development of therapeutic strategies. This review provides a detailed description of the role of lncRNAs and small molecules in the tumour microenvironment and their relationship with cancer stem cells. Thus, the potential of controlling lncRNAs and using anti-cancer small molecules in TME to improve the efficacy of cancer therapy was evaluated.

Recent studies have established the pivotal roles of patient-derived tumour organoids (PDTOs), innovative three-dimensional (3D) culture systems, in various biological and medical applications. PDTOs, as promising tools, have been established and extensively used for drug screening, prediction of immune response and assessment of immunotherapeutic effectiveness in various cancer types, including glioma, ovarian cancer and so on. The overarching goal is to facilitate the translation of new therapeutic modalities to guide personalised immunotherapy. Notably, there has been a recent surge of interest in the co-culture of PDTOs with immune cells to investigate the dynamic interactions between tumour cells and immune microenvironment. A comprehensive and in-depth investigation is necessary to enhance our understanding of PDTOs as promising testing platforms for cancer immunotherapy. This review mainly focuses on the latest updates on the applications and challenges of PDTO-based methods in anti-cancer immune responses. We strive to provide a comprehensive understanding of the potential and prospects of PDTO-based technologies as next-generation strategies for advancing immunotherapy approaches.

Tumour microenvironment harbours diverse stress factors that affect the progression of multiple myeloma (MM), and the survival of MM cells heavily relies on crucial stress pathways. However, the impact of cellular stress on clinical prognosis of MM patients remains largely unknown. This study aimed to provide a cell stress-related model for survival and treatment prediction in MM. We incorporated five cell stress patterns including heat, oxidative, hypoxic, genotoxic, and endoplasmic reticulum stresses, to develop a comprehensive cellular stress index (CSI). Then we systematically analysed the effects of CSI on survival outcomes, clinical characteristics, immune microenvironment, and treatment sensitivity in MM. Molecular subtypes were identified using consensus clustering analysis based on CSI gene profiles. Moreover, a prognostic nomogram incorporating CSI was constructed and validated to aid in personalised risk stratification. After screening from five stress models, a CSI signature containing nine genes was established by Cox regression analyses and validated in three independent datasets. High CSI was significantly correlated with cell division pathways and poor clinical prognosis. Two distinct MM subtypes were identified through unsupervised clustering, showing significant differences in prognostic outcomes. The nomogram that combined CSI with clinical features exhibited good predictive performances in both training and validation cohorts. Meanwhile, CSI was closely associated with immune cell infiltration level and immune checkpoint gene expression. Therapeutically, patients with high CSI were more sensitive to bortezomib and antimitotic agents, while their response to immunotherapy was less favourable. Furthermore, in vitro experiments using cell lines and clinical samples verified the expression and function of key genes from CSI. The CSI signature could be a clinically applicable indicator of disease evaluation, demonstrating potential in predicting prognosis and guiding therapy for patients with MM.

The tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) is complex and plays a role in prognosis and resistance to treatments. We aimed to decipher the iCCA TME phenotype using multiplex sequential immunohistochemistry (MS-IHC) to investigate which cell types and their spatial location may affect its prognosis. This was a retrospective study of 109 iCCA resected samples. For all cases, we used an open-source software to analyse a panel of markers (αSMA, FAP, CD8, CD163) by MS-IHC for characterize the different TME cells and their location. RNA sequencing was performed to determine the main iCCA transcriptomic classes. The association of the TME composition with overall survival (OS) was assessed by univariate and multivariate analyses. A high proportion of activated fibroblasts (FAP +) was significantly associated with poor OS (HR = 2.33, 95%CI = 1.43-3.81, p = 0.001). CD8 T lymphocytes excluded from the epithelial compartment were significantly associated with worse OS (HR = 1.86, 95% CI = 1.07-3.22, p = 0.014). The combination of a high proportion of FAP + fibroblasts and CD8 T lymphocytes excluded from the epithelial compartment, observed in 21 cases (19%), was significantly associated with poor OS on univariate (HR = 2.49, 95% CI = 1.44-4.28, p = 0.001) and multivariate analyses (HR = 2.77, 95% CI = 1.56-4.92, p < 0.001). In these cases, CD8 T lymphocytes were predominantly located at the tumour/non-tumour interface (19/21, 90%), and an association with the transcriptomic inflammatory stroma class was observed (10/21, 48%). Our results confirm the TME prognostic role in iCCA, highlighting the impact in the process of spatial heterogeneity, especially cell colocalization of immune and fibroblastic cells creating a peritumoural fibro-immune interface.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

BACKGROUND: Glioma is a brain tumour occurring in all age groups but common in adults. Despite advances in the understanding of tumours, we cannot improve the survival of the patients and do not have an appropriate biomarker for progression and prognosis prediction. The base excision repair mechanism maintains the integrity of the genome, preventing tumour formation. However, continuous chemical damage to the cells results in mutations that escape the repair mechanism and support tumour growth. The tumour microenvironment in cancer is crucial in determining the tumour growth, development, and response to treatments. The present study explored the significance of Base Excision Repair genes (BER) in modulating the tumour microenvironment.
METHODS: We used the publically available data sets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the role of the base excision repair gene in the modulating tumour microenvironment. The data was analysed for the expression of base excision repair genes, their correlation with the immune markers, their prognostic potential, and enrichment analysis to understand the pathways they modulate in low-grade glioma (LGG) progression.
RESULTS: The analysis showed BER genes contribute an integral role in the overall and disease-free survival of LGG. Genes like MUTYH, PNKP, UNG and XRCC1 showed a correlation with the immune infiltration levels and a significant correlation with various immune markers associated with different immune cells, including tumour-associated macrophages. MUTYH, UNG and XRCC1 correlated with IDH1 mutation status, and functional enrichment analysis showed that these genes are enriched in several pathways like Wnt, PD-1 and Integrin signalling.
CONCLUSIONS: Our findings suggest that the BER genes MUTYH, PNKP, UNG and XRCC1 can potentially be prognostic biomarkers and highly correlate with the immune cells of the tumour microenvironment.

Tumour endothelial cells (TECs) are genetically and phenotypically distinct from their normal, healthy counterparts and provide various pro-tumourigenic effects. This study aimed to investigate the impact of conditioned media (CM) from non-tumourigenic MCF-12A breast epithelial cells as well as from MCF-7 and MDA-MB-231 breast cancer cells on human umbilical vein endothelial cells (HUVECs). Significant increases in cell viability were observed across all breast CM groups compared to controls, with notable differences between the MCF-12A, MCF-7, and MDA-MB-231 groups. Despite increased viability, no significant differences in MCM2 expression, a marker of cell proliferation, were detected. Morphological changes in HUVECs, including elongation, lumen formation, and branching, were more pronounced in breast cancer CM groups, especially in the MDA-MB-231 CM group. qPCR and Western blot analyses showed increased expression of TEC markers such as MDR1, LOX, and TEM8 in HUVECs treated with MCF-12A CM. The MCF-7 CM group significantly enhanced HUVEC migratory activity compared to MCF-12A CM, as evidenced by a scratch assay. These findings underscore distinct angiogenic responses elicited by non-tumourigenic and tumourigenic breast epithelial cells, with tumourigenic cells inducing a hyperactivated angiogenic response. The study highlights the differential effects of breast cancer cell paracrine signalling on endothelial cells and suggests the need for further investigation into TEC markers\' role in both physiological and tumour angiogenesis.

UNASSIGNED: The significance of CXCL5 in pancreatic cancer is unclear, although it has been implicated in the malignant process of many different types of cancer. Research on the impact of CXCL5 on immune cell infiltration and the malignant phenotype of pancreatic cancer is needed. This study aimed to examine the connection between CXCL5 expression and immune cell infiltration and the malignant phenotype of pancreatic cancer.
UNASSIGNED: Tissue samples and clinical information were collected from 90 patients with pancreatic cancer. Tumour tissues and adjacent tissues were made into a tissue microarray and stained for immunohistochemistry analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to measure the expression level of CXCL5. CXCL5-overexpressing/CXCL5-knockdown cell lines were constructed via transfection for cytological experiments. CCK-8, cell apoptosis, cell cycle, cell invasion, and cell colony formation assays were used to detect the effect of CXCL5 on the malignant phenotype of pancreatic cancer cells. Finally, a mouse model of pancreatic cancer was constructed for in vivo verification.
UNASSIGNED: Compared with control cells, pancreatic cancer cells overexpressing CXCL5 exhibited increased proliferation, migration, and invasion but decreased apoptosis. Conversely, knockdown of CXCL5 did not enhance the malignant phenotype of pancreatic cancer cells. Spearman correlation analysis indicated that there was a significant negative correlation between CXCL5 levels and the CD8 IRS. However, there was a significant positive correlation between FOXP3 IRS and CXCL5 levels.
UNASSIGNED: CXCL5 is highly expressed in pancreatic cancer and promotes the malignant phenotype of pancreatic cancer cells. CXCL5 is associated with immunosuppressive FOXP3 + T-cell infiltration, which facilitates the formation of an immunosuppressive microenvironment (with low CD8 + T-cell infiltration).