ss hCG mediates immune suppression through upregulation of CD11b(+)Gr1(+) myeloid derived suppressor cells, CD206(+) M2 macrophages, and CD4(+)FOXP3(+) regulatory T-cells in BRCA1 deficient breast cancers

BRCA1 mutation is reported in about 70% of all triple negative breast cancers (TNBC), while BRCA1 defect due to promoter hypermethylation is seen in about 30%-60% of sporadic breast cancers. Although PARP inhibitors and platinum-based chemotherapy are used to treat these cancers, more efficient therapeutic approaches are required to overcome the resistance to treatment. Our previous findings have reported elevated ss hCG expression but not alpha hCG in BRCA1 deficient breast cancers. As ss hCG causes immune suppression in pregnancy, this study explored the immunomodulatory effect of ss hCG in BRCA1mutated/deficient TNBC. We observed that Th1, Th2, and Th17 cytokines are upregulated in the presence of ss hCG in BRCA1 defective cancers. In NOD-SCID and syngeneic mouse models, ss hCG increases the frequency of Myeloid-derived suppressor cells in tumour tissues and contributes to macrophage reprogramming from antitumor M1 to pro-tumour M2 phenotype. ss hCG reduces the CD4(+)T-cell infiltration while increasing the density of CD4(+)CD25(+)FOXP3(+)regulatory T-cell in BRCA1 deficient tumour tissues. In contrast, xenograft tumours with ss hCG knocked down TNBC cells did not show these immune suppressive effects. We have also shown that ss hCG upregulates pro-tumorigenic markers arginase1(Arg1), inducible nitric oxide synthase, PD-L1/PD-1, and NF kappa B in BRCA1 defective tumours. Thus, for the first time, this study proves that ss hCG suppresses the host antitumor immune response and contributes to tumour progression in BRCA1 deficient tumours. This study will help develop new immunotherapeutic approaches for treating BRCA1 defective TNBC by regulating ss hCG.

Automated summary

This study demonstrates that ss hCG suppresses the host antitumor immune response and contributes to tumour progression in BRCA1 deficient TNBC. These findings will aid in the development of new immunotherapeutic approaches for treating BRCA1 defective TNBC by regulating ss hCG.