Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma

Hodgkin lymphoma is a B cell derived malignancy characterized by a low number of tumor cells within an environment consisting of inflammatory cells. Recently, immune checkpoint blockade targeting the PD-1-PD-L1 axis has shown to be a great success in relapsed and refractory Hodgkin lymphoma patients. However, complete responses are scarce and median progression-free survival is limited to around 11-15 months. Efficiency of PD-1 blockade in HL might be dependent on CD4+ T cells, but also tumor associated macrophages (TAMs) and NK cells are implicated. The aim of this review is to highlight currently known prominent immune evasion strategies and discuss their possible contribution to primary or acquired resistance to immune checkpoint blockade in Hodgkin lymphoma. These include T cell dependent mechanisms such as shaping of the inflammatory infiltrate, lack of presentation of antigens and neoantigens and production of molecules involved in suppression of T cell functionality such as other immune checkpoints, indoleamine 2,3-dioxygenase and adenosine. Moreover, the role of NK cells and TAMs in efficient PD-1 blockade will be discussed. Targeting these mechanisms in parallel to PD-1 may potentially increase efficiency of PD-1 blockade therapy.