Figure 8. Anti-CSF-1R therapy overcomes PARP inhibitor-induced immune-suppressive macrophages and activates an anti-tumor immune response in BRCA-associated TNBC.
Schematic overview of PARP inhibitor-induced changes of tumor macrophages in BRCA-associated and proficient TNBC. In BRCA-associated TNBC: (1) Olaparib treatment induces cancer cell death (2), which leads to increased expression of CSF-1(3), leading to recruitment of monocyte to the tumor (4). (5) Olaparib enhances the differentiation of monocytes to macrophages and decreases glycolytic capacity and increase in PD-L1 expression in macrophages that is PARP1-independent. Olaparib increases the expression level of CSF-1R and pTBK1 in macrophages that is PARP1-dependent. Olaparib also induces expression of pro-inflammatory cytokines (IL-1β and TNF-α), DNA SSB repair response, and expression of co-stimulatory/activation molecules (CD86, CD80 and CD40) on macrophages. Fatostatin reverses the immune-suppressive phenotypic changes on macrophages caused by Olaparib. (6) Addition of anti-CSF-1R to Olaparib leads to an increase in M1-like macrophages and CTLs, which leads to tumor reduction. In the setting of BRCA-proficient TNBC, Olaparib does not induce cancer cell death and therefore there is attenuated tumor cell CSF-1 expression and no recruitment of monocytes to the tumor.