Characterisation of the tumour microenvironment and PD-L1 granularity reveals the prognostic value of cancer-associated myofibroblasts in non-invasive bladder cancer

Article

Author: Martínez, Victor G. ; Paramio, Jesús M. ; Munera-Maravilla, Ester ; Suárez-Cabrera, Cristian ; Martínez de Villarreal, Jaime ; Rodríguez Antolín, Alfredo ; Nunes, Sandra P. ; Guerrero-Ramos, Félix ; Sánchez, Rebeca ; Lora Pablos, David ; Dueñas, Marta ; Rubio, Carolina ; Perez Escavy, Mercedes ; Real, Francisco X. ; Cañizo, Carmen G. ; Lodewijk, Iris ; Castellano, Daniel ; Morales, Lucía ; Martín-Arriscado, Cristina ; Rodriguez-Izquierdo, Marta

High-risk non-muscle-invasive bladder cancer (NMIBC) presents high recurrence and progression rates. Despite the use of Bacillus Calmette-Guérin gold-standard immunotherapy and the recent irruption of anti-PD-1/PD-L1 drugs, we are missing a comprehensive understanding of the tumor microenvironment (TME) that may help us find biomarkers associated to treatment outcome. Here, we prospectively analyzed TME composition and PD-L1 expression of tumor and non-tumoral tissue biopsies from 73 NMIBC patients and used scRNA-seq, transcriptomic cohorts and tissue micro-array to validate the prognostic value of cell types of interest. Compared to non-tumoral tissue, NMIBC presented microvascular alterations, increased cancer-associated fibroblast (CAF) and myofibroblast (myoCAF) presence, and varied immune cell distribution, such as increased macrophage infiltration. Heterogeneous PD-L1 expression was observed across subsets, with macrophages showing the highest expression levels, but cancer cells as the primary potential anti-PD-L1 binding targets. Unbiased analysis revealed that myoCAF and M2-like macrophages are specifically enriched in high-grade NMIBC tumors. The topological distribution of these two cell types changed as NMIBC progresses, as shown by immunofluorescence. Only myoCAFs were associated with higher rates of progression and recurrence in three independent cohorts (888 total patients), reaching prediction values comparable to transcriptomic classes, which we further validated using tissue micro-array. Our study provides a roadmap to establish the landscape of the NMIBC TME, highlighting myoCAFs as potential prognostic markers.

31 Dec 2025·OncoImmunology

Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade

Article

Author: Navarro-Gorro, Nil ; Del Rey-Vergara, Raúl ; Berenguer-Molins, Pau ; Perera-Bel, Júlia ; White, James ; Arriola, Edurne ; Jackson, Jennifer B ; Masfarré, Laura ; Hardy-Werbin, Max ; Rocha, Pedro ; Lu, Wei ; Sausen, Mark ; Taus, Álvaro ; Clavé, Sergi ; Galindo, Miguel ; Rovira, Ana ; Hernandez, Sharia ; Chalela, Roberto ; Villanueva, Xavier ; Soto, Luisa M Solis ; Bach, Rafael ; Iñañez, Albert ; Sanchéz, Ignacio ; Acedo-Terrades, Ariadna ; Curull, Victor ; Bellosillo, Beatriz ; Sanchéz-Espiridion, Beatriz ; Rossell, Adrià ; Sánchez-Font, Albert ; Giner, Mario ; Georgiadis, Andrew ; Moliner, Laura ; Wistuba, Ignacio

INTRODUCTIONImmunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.METHODSA total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.RESULTSOur analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.CONCLUSIONSOur multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.

01 Jul 2025·Biomaterials Advances

Co-culture of multiple myeloma cell lines and bone marrow mesenchymal stem cells in a 3D microgel environment

Article

Author: Sempere, Amparo ; Tolosa, Laia ; Plá-Salom, Júlia ; Cordón, Lourdes ; García-Briega, M Inmaculada ; Clara-Trujillo, Sandra ; Ribelles, José Luís Gómez

This study reproduces the complex relationships between tumour plasma cells and their bone marrow microenvironment in multiple myeloma in vitro. These relationships are established both with other cells and with the extracellular matrix and are key factors in tumour progression, generating resistance to antitumour drugs in the cellular and non-cellular environments. This paper proposes a 3D microenvironment model designed to capture the main components of the multiple myeloma tumour microenvironment. Multiple myeloma cells (MMCs) were dispersed in a microgel medium formed by gel-textured microspheres. The proteins and polysaccharides considered important in the interaction of the MMCs with their non-cellular environment were successfully grafted onto the surface of the microspheres, while human mesenchymal stem cells (MSCs) were cultured in a pellet with non-functionalised microspheres. The MSCs pellet was placed in the well plate together with the microgel and the MMCs and orbitally shaken to maintain them in suspension. The viability, cell cycle and proliferation of the RPMI8226, MM1S and U266 multiple myeloma cell lines and the direct adhesion of MMCs to the MSC pellet were quantified. The results revealed that all three cell lines are able to grow satisfactorily. In addition, the normal behaviour of the MMCs is not modified in any of the culture conditions studied.

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