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Mapping the immune heterogeneity within the tumor microenvironment to identify novel target populations for immunotherapy in multiple myeloma
Book - Dissertation
Abstract:Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM). Despite significant therapeutic advances over the past decades, MM remains incurable. Understanding the complex tumor-immune microenvironment (TME) has emerged as a key step toward designing more effective and durable immunotherapies. Single-cell RNA sequencing (scRNA-seq) represents a powerful tool to dissect the cellular and molecular dynamics within the MM-TME during disease progression at high-level resolution.
In this thesis, we implemented scRNA-seq on BM and spleen samples from the 5T33MM mouse model. Comparative analysis with human MM datasets further strengthened the translational relevance of our findings. Our scRNA-seq data revealed profound remodeling of the immune compartment, characterized by an accumulation of exhausted T cells, pro-tumorigenic neutrophils, and impaired activation of conventional dendritic cells (cDCs). Finally, these dynamic changes during MM-disease progression were validated by multi-parameter flow cytometry.
Dendritic cells (DCs) have emerged as interesting players to boost anti-tumor immunity, given their crucial role in initiating and sustaining T-cell responses. However, in MM, cDCs exhibited impaired activation. In our preclinical 5T33MM model, treatment with an anti-CD40 agonist (αCD40) restored cDC activation, boosted T-cell responses, and achieved significant but transient tumor control.
To further potentiate DC-mediated immunity, we investigated Flt3-Flt3L signaling. Flt3 was selectively expressed on DC subsets, with minimal expression on MM cells, making it an attractive strategy to selectively expand DC populations without promoting MM cell growth. Although Flt3L expanded DC populations ex vivo, it failed to reduce tumor burden in vivo and instead increased regulatory T cells. Moreover, combining Flt3L with αCD40 provided no additional benefit, underscoring the need for alternative combination approaches.
An alternative approach to improve therapeutic efficacy is to combine DC-boosting approaches with direct MM cell killing. Panobinostat, an approved histone deacetylase inhibitor for the treatment of MM and known for its ability to induce immunogenic cell death, activated cDCs and demonstrated additive effects with αCD40, although further in vivo validation is required.
In conclusion, this study provides a comprehensive immune atlas of MM progression in both human and murine models, identifying cDC dysfunction as a critical barrier to effective anti-tumor immunity. Our findings highlight DC-targeted strategies as a promising approach to strengthen immune-based therapies for MM.
In this thesis, we implemented scRNA-seq on BM and spleen samples from the 5T33MM mouse model. Comparative analysis with human MM datasets further strengthened the translational relevance of our findings. Our scRNA-seq data revealed profound remodeling of the immune compartment, characterized by an accumulation of exhausted T cells, pro-tumorigenic neutrophils, and impaired activation of conventional dendritic cells (cDCs). Finally, these dynamic changes during MM-disease progression were validated by multi-parameter flow cytometry.
Dendritic cells (DCs) have emerged as interesting players to boost anti-tumor immunity, given their crucial role in initiating and sustaining T-cell responses. However, in MM, cDCs exhibited impaired activation. In our preclinical 5T33MM model, treatment with an anti-CD40 agonist (αCD40) restored cDC activation, boosted T-cell responses, and achieved significant but transient tumor control.
To further potentiate DC-mediated immunity, we investigated Flt3-Flt3L signaling. Flt3 was selectively expressed on DC subsets, with minimal expression on MM cells, making it an attractive strategy to selectively expand DC populations without promoting MM cell growth. Although Flt3L expanded DC populations ex vivo, it failed to reduce tumor burden in vivo and instead increased regulatory T cells. Moreover, combining Flt3L with αCD40 provided no additional benefit, underscoring the need for alternative combination approaches.
An alternative approach to improve therapeutic efficacy is to combine DC-boosting approaches with direct MM cell killing. Panobinostat, an approved histone deacetylase inhibitor for the treatment of MM and known for its ability to induce immunogenic cell death, activated cDCs and demonstrated additive effects with αCD40, although further in vivo validation is required.
In conclusion, this study provides a comprehensive immune atlas of MM progression in both human and murine models, identifying cDC dysfunction as a critical barrier to effective anti-tumor immunity. Our findings highlight DC-targeted strategies as a promising approach to strengthen immune-based therapies for MM.
Number of pages: 201
Publication year:2025
Accessibility:Embargoed