Biology subjects

Sirven, P.

Publications and source records attributed to Sirven, P..

5 recordsLinked to original sources

bioRxiv2025

Analysis of intratumoral immune heterogeneity reveals spatial organisation of immunosuppression in breast cancer

Recent advances in single-cell transcriptomics have illuminated intratumoral heterogeneity (ITH) in breast cancer, yet the spatial organization and functional states of immune populations within luminal tumors remain poorly understood. Here, we generated a spatially and clonally resolved single-cell immune atlas of early-stage luminal breast cancer by integrating paired single-cell RNA/TCR sequencing with multiplex immunohistochemistry across three spatially distinct tumor regions: central (core-proximal), intermediate and peripheral (invasive margin-proximal), in five patients. Peripheral regions are enriched in naive CD4 T cells, monocytes, dendritic cells, and memory CD8 T cells with bystander properties, alongside TCF1+ exhausted progenitors (Tpex), and displayed elevated antigen presentation and tertiary lymphoid structures (TLS) signatures. In contrast, central regions harbor macrophages, clonally expanded regulatory T cells (Tregs), and two subsets of terminally exhausted CD8 T cells (Tex), one tissue-resident and one circulating, both expressing tumor-reactive features. Clonal overlap was observed between peripheral Tpex and central, tissue-resident Tex cells, revealing a spatially confined differentiation trajectory toward exhaustion within the tumor microenvironment. Central T cells also upregulate TGF-{beta} signaling and metabolic pathways including fatty acid oxidation and oxidative phosphorylation, consistent with adaptation to an immunosuppressive microenvironment. Together, these findings reveal a spatially structured immune landscape in luminal breast cancer, marked by progressive immunosuppression from the tumor margin to the core, providing a framework for future region-specific immunotherapeutic strategies.

immunology↗

bioRxiv2024

How cancer-associated fibroblasts promote T cell exclusion in human lung tumors: a physical perspective

The tumor stroma is a tissue composed primarily of extracellular matrix, fibroblasts, immune cells, and vasculature. Its structure and functions, such as nutrient support and waste removal, are altered during malignancy. Tumor cells transform fibroblasts into cancer-associated fibroblasts, which have important immunosuppressive activity on which growth, invasion, and metastasis depend. These activated fibroblasts prevent immune cell infiltration into the tumor nest, thereby promoting cancer progression and inhibiting T-cell-based immunotherapy. To understand these complex interactions, we measure the density of different cell types in the stroma using immunohistochemistry techniques on tumor samples from lung cancer patients. We incorporate these data, and also known information on cell proliferation rates and relevant biochemical interactions, into a minimal dynamical system with few parameters. A spatio-temporal approach to the inhomogeneous environment explains the cell distribution and fate of lung carcinomas. The model reproduces that cancer-associated fibroblasts act as a barrier to tumor growth, but also reduce the efficiency of the immune response. The final outcome depends on the parameter values for each patient and leads to either tumor invasion, persistence, or eradication as a result of the interplay between cancer cell growth, T-cell cytotoxic activity, and fibroblast attraction, activation, and spatial dynamics. Our conclusion is that a wide spectrum of scenarios exists as a result of the competition between the characteristic times of cancer cell growth and the activity rates of the other species. Nevertheless, distinct trajectories and patterns allow quantitative predictions that may help in the selection of new therapies and personalized protocols. We conclude with different options for further modeling. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/575824v3_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@156ac4forg.highwire.dtl.DTLVardef@14a9a19org.highwire.dtl.DTLVardef@cafebeorg.highwire.dtl.DTLVardef@11aa3bf_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

biophysics↗

bioRxiv2022

Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors

It is currently accepted that activated cancer-associated fibroblasts (CAF) participate in T cell exclusion from tumor nests, but it remains unclear how they promote barrier phenotypes, and whether specific subsets are involved. Here, using single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors, we identify four main CAF populations, of which only two are associated with T cell exclusion: (i) MYH11+SMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+SMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both CAF populations show a contractility phenotype together with dense and aligned matrix fiber deposition compared to the T cell-permissive CAF. Yet they express distinct matrix genes, including COL4A1/COL9A1 (MYH11+SMA+ CAF) and COL11A1/COL12A1 (FAP+SMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCEThe cellular and molecular programs driving T cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to develop new strategies targeting T cell-excluding CAF.

cancer biology↗

bioRxiv2019

MMP2 As An Independent Prognostic Stratifier In Oral Cavity Cancers

BackgroundAround 25% of oral cavity squamous cell carcinoma (OCSCC) are not controlled by standard of care. Identifying those patients could offer them possibilities for intensified and personalized regimen. However, there is currently no validated biomarker for OCSCC patient selection in a pre-treatment setting.\n\nPatients and methodsOur objectives were to determine a robust and independent predictive biomarker for disease related death in OCSCC treated with standard of care. Tumor and juxtatumor secretome were analyzed in a prospective discovery cohort of 37 OCSCC treated by primary surgery. Independent biomarker validation was performed by RTqPCR in a retrospective cohort of 145 patients with similar clinical features. An 18-gene signature (18G) predictive of the response to PD-1 blockade was evaluated in the same cohort..\n\nResultsAmong 29 deregulated molecules in a secretome analysis, we identified soluble MMP2 as a prognostic biomarker. In our validation cohort (n=145), high levels of MMP2 and CD276, and low levels of CXCL10 and STAT1 mRNA were associated with poor prognosis in univariate analysis (Kaplan-Meier). MMP2 (p = 0.001) and extra-nodal extension (ENE) (p = 0.006) were independent biomarkers of disease-specific survival (DSS) in multivariate analysis, and defined prognostic groups with 5-year DSS ranging from 36% (MMP2highENE+) to 88% (MMP2lowENE-). The expression of 18G was similar in the different prognostic groups, suggesting comparable responsiveness to anti-PD-1.\n\nConclusionHigh levels of MMP2 was an independent and validated prognostic biomarker, which may be used to select poor prognosis patients for intensified neoadjuvant or adjuvant regimens.

cancer biology↗

bioRxiv2019

PDL1 AND ICOSL DISCRIMINATE HUMAN SECRETORY AND HELPER DENDRITIC CELLS

Dendritic cells (DC) are described as immature at the steady state, with a high antigen capture capacity, turning into a mature state with a strong T cell stimulatory capacity upon activation. Using 16 different stimuli in vitro (130 observations), we describe two states of human activated dendritic cells. PDL1highICOSLlow \"secretory DC\" produced large amounts of inflammatory cytokines and chemokines but induced very low levels of T helper (Th) cytokines following DC-T co-culture; conversely PDL1lowICOSLhigh \"helper DC\" produced low levels of secreted factors but induced high levels of Th cytokines characteristic of a broad range of Th subsets. Secretory DC were phenotypically identified in T cell inflamed primary head and neck squamous cell carcinoma. RNAseq analysis showed that they expressed a typical secretory DC signature, including CD40, PVR, IL1B, TNF, and CCL19. This novel and universal functional dichotomy of human DC opens broad perspectives for the characterization of inflammatory diseases, and for immunotherapy.

immunology↗