Prendeville, S. | Search bioRxiv

bioRxiv2026

Multimodal cell communication networks nominate immunotherapies for RCC subgroups with discrete T cell recruitment or expansion

Renal cell carcinoma (RCC) is amongst the most immune-infiltrated solid tumours, but only a small subset of patients achieves durable response to immune checkpoint blockade therapy. Efforts to characterize the immune microenvironment and molecular regulators responsible for treatment responses have explored numerous facets of disease biology using compartmentalized genomics, transcriptomics, and proteomics datasets, yielding many important yet context and data specific insights. Therefore, to provide a more integrated approach to informing future precision medicine strategies, we combined the complementary strengths of multiple technological platforms to profile multi-regional, spatially annotated surgical biospecimens from 65 RCC patients by single-cell RNA sequencing with paired TCR and BCR repertoire analysis, imaging mass cytometry, suspension mass cytometry, spatial transcriptomics and deconvolved bulk RNA sequencing. With this resource dataset, we explored patient subgroups and precision immunotherapy strategies using an integrated analysis of transcripts and proteins across single cell and spatial modalities. Proximal cell interactions and distinct receptor-ligand pairings identified 7 recurrent cellular communication networks. Robustly mapping reproducible gene signatures across technologies and to a variety of publicly available datasets, we show these highly refined immune subgroups stratify patients with tumour microenvironments associated with prognosis and immunotherapy response. Notably, this reveals that highly infiltrated environments with the potential for immunotherapy response may in fact comprise two distinct communication networks, with differing modes of T cell clonal expansion and immune evasion axes associated with T cell exhaustion or myeloid and NK reprogramming, which could inform targeted combination therapeutic strategies to improve outcomes. Overall, we provide a high-dimensional multi-modal resource dataset that enables cross-platform integration, links stages of T cell clonal expansion with enabling or suppressive RCC immune cell communication networks and nominates rational strategies for combinatorial precision immunotherapy. (Funded by University Health Network, Toronto; REMEDY ClinicalTrials.gov number, NCT04005183.)

cancer biology↗

bioRxiv2026

Humanized patient-derived xenografts preserve tumour-specific immune microenvironments

Defining the genetic and cellular programs that allow solid tumours to evade immune control requires preclinical models that preserve the complexity of the human tumour immune microenvironment. Most available systems capture only part of this biology. Organoid cultures and ex vivo tumour fragments can retain patient-derived tumour architecture and associated immune cells, but immune populations are typically maintained only for short periods. These models also cannot capture antitumour immune responses in the physiological setting of a living organism. Patient-derived xenografts propagated in humanized mice offer a potential path to overcome these limitations by combining patient-derived tumour tissue with a reconstituted human immune system. However, few studies have systematically tested whether these models reproduce the diverse immune cell phenotypes present in the parental tumours from which they are derived. This has limited their use for studying tumour-intrinsic mechanisms that shape immune composition and promote immune evasion. To address this gap, we profiled tumour-infiltrating, splenic, and bone marrow immune cells from ovarian, head and neck, and renal PDX models propagated in CD34+ hematopoietic stem cell (HSC)-derived huNOG-EXL mice expressing human IL-3 and GM-CSF. By comparing tumours grown across distinct HSC donor backgrounds with their matched primary tumour samples, we found that tumour-intrinsic factors are a dominant determinant of immune composition in humanized PDX tumours. Across models, these immune infiltrates generally resembled those of the corresponding parental tumours. These findings support humanized PDX models as a platform for functionally interrogating tumour-intrinsic drivers of immune composition and immune evasion in solid tumours.

cancer biology↗