Macrophages and T cells in classic Hodgkin lymphoma
Macrophages and T cells in classic Hodgkin lymphoma
Classic Hodgkin lymphoma is a blood cancer that mainly affects young adults. Although cancer cells make up less than 5% of the tumor, they can manipulate the abundant immune cells in the surroundings to support tumor growth and enable immune escape. PD-1 checkpoint blockade is a treatment that can restore anti-tumor immunity, but not all patients respond and durable cures remain challenging.
This thesis of Rodrigo Martinez Alcala investigated how the tumor microenvironment influences disease behavior and response to PD-1 blockade, focusing on tumor-associated macrophages (TAMs). First, three candidate tissue biomarkers, c-MET, HLA class II and CD68, were evaluated in samples from an international clinical trial. None reliably predicted patient outcomes, underscoring the need for rigorous biomarker validation.
Next, imaging mass cytometry was used to generate a high-quality single-cell dataset comprising over one million cells from samples of 69 patients. As a proof of concept, PD-L1 expression was profiled on tumor cells and TAMs. PD-L1 was more frequently expressed by TAMs than by tumor cells, and a reproducible analytical framework was established for future spatial studies of PD-1 and other checkpoint pathways.
Finally, laboratory models demonstrated that PD-1 blockade primarily enhances CD4 T-cell activation. Moreover, cancer cells were shown to drive monocyte differentiation into immunosuppressive, PD-L1-positive macrophages. These macrophages suppressed immune-cell activity but also modulated responses to PD-1 blockade. Collectively, these findings demonstrate that both malignant cells and the surrounding immune microenvironment shape treatment response, providing a foundation for developing more personalized and effective immunotherapies for Hodgkin lymphoma.