Fig. 1.

Potential Mechanisms of synergy of anti-PD-1/L1 combination therapies. a Standard-of-care therapies in the metastatic breast cancer setting exhibit varied and overlapping immunomodulatory effects that may promote therapeutic synergy with anti-PD-1/L1; b Immunogenic cell death is conserved across a number of anti-neoplastic modalities. A hallmark biologic feature is calreticulin exposure from the endoplasmic reticulum, resulting in downstream antigen presentation, T-cell activation, and adaptive PD-L1 upregulation; c Another common mechanism of synergy is PD-L1 upregulation, which can occur via modulation of a variety of molecular pathways. PD-L1: programmed death ligand 1; MDSC: myeloid derived suppressor cell; Treg: T-regulatory cell; MHC: major histocompatibility complex; ADCC: antibody-dependent cellular cytotoxicity; NK: natural killer; CDK4/6: cyclin-dependent kinase 4/6; HER2: human epidermal growth factor receptor 2; mTOR: mammalian target of rapamycin; PARP; poly(ADP ribose) polymerase; ATP: adenosine triphosphate; HMGD1: high mobility group box 1; HSPs: heat shock proteins; IFNγ: interferon gamma; NFκB: nuclear factor kappa-light-chain enhancer of activated B-cells; PAMP: pathogen-associated molecular pattern; TLR: toll like receptor; TRAF6: TNF receptor associated factor 6; JNK: c-Jun N-terminal kinase; NFAT: nuclear factor of activated T-cells; IFNGR1/2: interferon gamma receptor 1/2; STAT: signal transducer and activator of transcription protein; IRF: interferon regulatory factor; PI3K: phosphoinositide 3-kinase; PIP3: phosphatidylinositol (3,4,5)-triphosphate; AKT: protein kinase B; eIF4B: eukaryotic translation initiation factor 4B