Background: Given the scarcity of effective therapeutic targets, metastatic triple negative breast cancer (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.
Methods: We employed single cell RNA sequencing (scRNAseq), 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.
Results: Transcriptomic analysis reveal divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, is characterized by an immune-promoting CD33+ cell phenotype involving IL1b signaling compared to non-responders, where an immunosuppressive phenotype marked by IL1b inhibition is observed. These baseline differences become more pronounced during the course of chemo-immunotherapy. Differences in CD33+ cell phenotype result in functional differences in lymphocyte activities between responders and non-responders. Depletion of CD33+ cells in pre-treatment samples from non-responders, restores T cell effector function.
Conclusion: 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.
Advanced triple-negative breast cancer is challenging to treat because it does not respond to treatments used for other types of breast cancer. A treatment that has seen some benefit is combining chemotherapy with drugs that help the immune system fight the cancer (immunotherapy). Our study analyzed blood samples from patients before and during immunotherapy to better understand why some patients respond better to the treatment than others. We looked at proteins produced by cells involved in immunity and found that a type of immune cell called CD33+ myeloid suppressor cells behaved differently in patients who responded to treatment compared to non-responding patients. In responding patients, these cells helped to activate the immune system to fight cancer, while in non-responders, they suppressed the immune system. This discovery could lead to new strategies to improve the effectiveness of immunotherapy that target these cells to make immunotherapy more effective against triple negative breast cancer.
© 2025. The Author(s).