Periodic Reporting for period 1 - SESAHME (Spatially rEsolved Single-cell Approaches in Haematologic MalignanciEs)
Reporting period: 2022-09-01 to 2024-08-31
Bone marrow is the soft tissue that fills bone cavities and constitutes the primary site of blood cell production. However, it is also one of the most complex niches in which cancerous cells accumulate. Multiple myeloma, the second most common blood cancer, is a paradigm of a tumor in which malignant plasma cells interact with a bone marrow microenvironment. Additionally, novel immunotherapeutic strategies, that target multiple myeloma cells in a complex interplay with immune cells in their microenvironment, highly depend on the bone marrow microenvironment composition. Accordingly, understanding the immunomodulating effects of drugs and the patient-specific contributions of the bone marrow microenvironment to therapy response are emerging as critical aspects for advancing treatment. However, our current understanding of bone marrow microenvironment heterogeneity and dynamics in multiple myeloma is limited. Risk stratification models and treatment strategies are primarily based on tumor genetics and clinical factors. They fail to fully account for the influence of the bone marrow microenvironment on disease progression and treatment response. SESAHME addresses this gap by comprehensively mapping a healthy and dysfunctional bone marrow microenvironment that can contribute to cancer development or promote disease progression and drug resistance. This could lead to advanced immunotherapy approaches in the future.
SESAHME developed a low-cost high-throughput experimental and data analysis workflow to reliably trace bone marrow microenvironment composition and dynamics in patients over several years as part of a phase III clinical trial with comparable study design and an extensive clinical data set. The methods previously available led to experimental shifts when measuring large sample numbers, which made sample comparisons across experimental runs unreliable. SESAHME established experimental controls and utilized physics-informed models of instrument characteristics on one hand and dye chemistry on the other hand to greatly improve comparability of data taken at different time points. This made it possible to create a massive atlas of the human bone marrow with more than 500 Mio single cells, comprising more than 2,000 samples from over 500 individuals. In contrast to previous studies, which were constrained to approximately 1 Mio single cells and a single time point, SESAHME’s study set-up made it possible to longitudinally track patients at up to six time-points over a period of four years. Accordingly, it deciphers bone marrow microenvironment dynamics at an unprecedented resolution and extensive samples size allowing for sophisticated comparisons and correlations such as with patient clinical parameters.
This work goes beyond the state of the art as SESAHME identified a relationship between bone marrow microenvironment heterogeneity and clinical outcome. Patients exhibit significant compositional heterogeneity of the bone marrow microenvironment driven by distinct patterns of cell types and cellular states, which influences subsequent bone marrow microenvironment changes during therapy ultimately affecting treatment response. Different bone marrow microenvironment changes for distinct drugs and depending on the timing of the drug were identified. In the future, this may enable clinicians to exploit bone marrow microenvironment information for multiple myeloma patient stratification and monitoring during cancer therapy. While the findings are currently limited to the specific therapies trialled as part of a phase III clinical trial, transfer of our approach to other immunotherapies and disease entities with tumor microenvironment involvement is planned. Additionally, the established experimental and data analysis workflow opens vast opportunities for other sample types, disease areas and basic research fields. To ensure further uptake and success this requires effective communication to relevant research communities.