Biology subjects

Gandini, A.

Publications and source records attributed to Gandini, A..

3 recordsLinked to original sources

bioRxiv2026

Reprogramming tumour-associated macrophages from immune suppressive to inflammatory state by Checkpoint kinase 1 inhibitor combination treatment

BackgroundTumour-associated macrophages (TAMs) play critical roles within the tumour microenvironment regulating immune evasion and therapeutic response. Previously, we have shown that the combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea (LDHU) reprograms the tumour immune microenvironment to a pro-inflammatory status. MethodsWe investigated a tumour-restricted Fcgr4 (Cd16.2) expressing macrophage population in multiple murine tumour models and the impact of CHK1i+LDHU on this population, using conventional and imaging flow cytometry as well as single-cell sequencing. ResultsTranscriptional profiling using CITE-seq and single-cell RNA sequencing reveals that Fcgr4 TAMs closely resemble Fcgr4- TAMs but display modest enrichment of interferon-associated and inflammatory gene programs, consistent with a functionally biased state rather than a distinct lineage. Importantly, we show that a highly tumour selective CHK1i+LDHU therapy shifts TAMs toward a more inflammatory phenotype while preserving dominant immunosuppressive features. Depletion of CSF1R macrophages enhanced CD8 T cell activation without influencing tumour growth but significantly augmented therapeutic efficacy of CHK1i+LDHU. ConclusionTogether, these findings define a novel TAM population and establish how targeted therapy reshapes, but does not fully overcome, TAM-mediated immune regulation.

cancer biology↗

bioRxiv2025

Using targeted therapy to promote a pro-inflammatory tumour microenvironment and anti-tumour immune response in high grade serous ovarian cancer

BACKGROUNDHigh-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-dose hydroxyurea (LDHU) promotes a unique ATR-independent moderate replication stress response with potent anti-tumour effects. The ability of this approach to reprogram the tumour immune microenvironment (TIME) to overcome the immunosuppression and promote an anti-tumour immune response in HGSOC is the focus of this study. METHODSWe investigated the therapeutic potential of CHK1i+LDHU in established HGSOC cell cultures, fresh tumour cell explants from HGSOC patient ascites, and syngeneic mouse models, assessing tumour cell killing, immunogenic cell death, pro-inflammatory cytokine/chemokine expression, and anti-tumour immune responses. RESULTSCHK1i+LDHU effectively killed ovarian cancer cells regardless of chemotherapy resistance, BRCA2 mutation and homologous recombination repair status in vitro. In vivo, treatment significantly reduced tumour burden and ascites accumulation. CHK1i+LDHU enhanced expression of pro-inflammatory cytokines/chemokines and triggered immunogenic cell death in tumour. In syngeneic models, treatment promoted CD8+ cytotoxic T cell-dependent anti-tumour responses and reduced immunosuppressive signalling within the TIME. CONCLUSIONSCHK1i+LDHU is a promising therapy for chemotherapy-resistant HGSOC, combining direct cytotoxic effects with reprogramming the TIME to reduce immunosuppression and activate a CD8+ T cell-dependent anti-tumour response.

cancer biology↗

bioRxiv2024

A reliance on human habitats is key to the success of an introduced predatory reptile

Understanding the success of animals in novel environments is increasingly important as human-mediated introductions continue to move species far beyond their natural ranges. Alongside these introductions, inhabited and agricultural areas are spreading, and correspondingly most animal introductions occur in populated areas. Commensal species which can live alongside humans by making use of specific conditions, structures, or prey, have a significant advantage. Introduced mammal species often use anthropogenic features in their environment and demonstrate a higher tolerance of human disturbance, but their importance remains understudied in ectotherms. The Aesculapian snake (Zamenis longissimus) is an ectotherm which has been introduced beyond the northern extremities of its natural range. To understand their persistence, we radio-tracked snakes daily over two active seasons, including high-frequency tracking of a subset of males. We investigated snake home range size using Autocorrelated Kernel Density Estimators (AKDE). Using AKDE-weighted Habitat Selection Functions we identified preferences for habitat features in a mosaic of habitats, and we used Integrated Step Selection Functions to further explore how these features influence movement. We revealed a particular preference for buildings in male snakes, while females preferred woodland. We demonstrate that the success of this ectothermic predator is likely tied to a willingness to use human features of the landscape.

animal behavior and cognition↗