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Updated: May 6, 2026
Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy
Published on: October 6, 2014
Mapping intratumoral myeloid-T cell interactomes at single-cell resolution reveals targets for overcoming checkpoint
Kate Bridges1,2, Gabriela A Pizzurro1, Alev Baysoy1
1Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
Abstract:
Effective cancer immunotherapies restore anti-tumor immunity by rewiring cell-cell communication. Treatment-induced changes in communication can be inferred from single-cell RNA-sequencing (scRNA-seq) data, but current methods do not effectively manage heterogeneity within cell types. Here we developed a computational approach to efficiently analyze scRNA-seq-derived, single-cell-resolved cell-cell interactomes, which we applied to determine how agonistic CD40 (CD40ag) alters immune cell crosstalk alone, across tumor models, and in combination with immune checkpoint blockade (ICB). Our analyses suggested that CD40ag improves responses to ICB by targeting both immuno-stimulatory and immunosuppressive macrophage subsets communicating with T cells, and we experimentally validated a spatial basis for these subsets with immunofluorescence and spatial transcriptomics. Moreover, treatment with CD40ag and ICB established coordinated myeloid-T cell interaction hubs that are critical for reestablishing antitumor immunity. Our work advances the biological significance of hypotheses generated from scRNA-seq-derived cell-cell interactomes and supports the clinical translation of myeloid-targeted therapies for ICB-resistant tumors.
Insights
Agonistic CD40 therapy enhances responses to immune checkpoint blockade by reprogramming macrophage and T cell communication. This rewiring creates crucial myeloid-T cell interaction hubs, vital for restoring anti-tumor immunity in resistant cancers.
Area of Science:
- Immunology
- Computational Biology
- Cancer Research
Background:
- Cancer immunotherapies rely on modulating cell-cell communication to restore anti-tumor immunity.
- Single-cell RNA sequencing (scRNA-seq) offers insights into cellular communication but struggles with cell type heterogeneity.
- Understanding treatment-induced communication changes is key for improving cancer therapies.
Purpose of the Study:
- To develop a computational method for analyzing single-cell interactomes from scRNA-seq data, addressing cell type heterogeneity.
- To investigate how agonistic CD40 (CD40ag) therapy impacts immune cell crosstalk, alone and with immune checkpoint blockade (ICB).
- To identify therapeutic strategies for ICB-resistant tumors by understanding myeloid-T cell interactions.
Main Methods:
- Development of a novel computational approach for analyzing single-cell resolved cell-cell interactomes from scRNA-seq data.
- Application of the method to analyze CD40ag treatment effects across different tumor models and in combination with ICB.
- Experimental validation using immunofluorescence and spatial transcriptomics to confirm findings on macrophage subsets and spatial interactions.
Main Results:
- CD40ag therapy was found to target both stimulatory and suppressive macrophage subsets that communicate with T cells, thereby enhancing ICB responses.
- A spatial basis for these macrophage subsets was experimentally validated.
- Combined CD40ag and ICB treatment led to the formation of coordinated myeloid-T cell interaction hubs, essential for re-establishing anti-tumor immunity.
Conclusions:
- The developed computational method effectively analyzes cell-cell interactomes, advancing the biological significance of scRNA-seq derived hypotheses.
- CD40ag therapy shows promise in improving ICB efficacy by modulating myeloid-T cell crosstalk.
- These findings support the clinical translation of myeloid-targeted therapies for overcoming ICB resistance in cancer treatment.
