Responses to checkpoint inhibition in metastatic TNBC driven by divergent myeloid phenotypes

Due to scarcity of effective therapeutic targets, metastatic TNBC (mTNBC) has shorter survival times compared to other advanced breast cancer subtypes. Although chemo-immunotherapy with immune checkpoint inhibitors (ICIs) in PD-L1+ mTNBC has shown promise, survival benefit remains modest. Therefore, it is crucial to gain improved insight into the mechanisms underlying response and resistance to checkpoint inhibition in mTNBC. We employed single cell-RNA-sequencing, single cell secretomics, and flow cytometry to identify transcriptomic and proteomic peripheral immune cell signatures associated with response and non-response to anti-PD-1/PD-L1 therapy and chemotherapy in mTNBC. Transcriptomic analysis revealed divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, was characterized by an immune-promoting CD33+ cell phenotype involving IL-1b signaling versus, in non-responders, an immunosuppressive phenotype marked by IL-1b inhibition. These baseline differences expanded during the course of treatment. Differences in CD33+ cell phenotype resulted in functional differences in lymphocyte activities between responders and non-responders. To confirm this causal role of myeloid cells, we depleted CD33+ cells in pre-treatment samples from non-responders, which led to a rescue of T cell effector function. Our findings highlight CD33+ cell phenotype as a key determinant of response to chemo-immunotherapy, which can be assessed from peripheral blood. This offers a valuable tool in the context of metastatic TNBC, in which tissue sampling is often challenging.