PD-L1 blockade immunotherapy alters cancer emergency myelopoiesis

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (aPDL1) in tumour-bearing mice, targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), mediating their exit from dormancy and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces a transcriptomic reprogramming of HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumor-bearing mice, shifting towards an inflammatory state. Functionally, transplantation of ex vivo isolated aPDL1-treated HSPCs exhibited an altered potential of cancer emergency myelopoiesis as evident by the reduced frequencies of myeloid-derived suppressor cell (MDSCs) compared to control-treated HSPCs. Overall, our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer which entails targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis.