S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition

Begg, L. R.; Orriols, A. M.; Zannikou, M.; Yeh, C.; Vadlamani, P.; Kanojia, D.; Bolin, R.; Dunne, S. F.; Balakrishnan, S.; Camarda, R.; Roth, D.; Zielinski-Mozny, N. A.; Yau, C.; Vassilopoulos, A.; Huang, T.-H.; Kim, K.-Y. A.; Horiuchi, D.

doi:10.1101/2023.09.21.558870

bioRxiv · 10.1101/2023.09.21.558870

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition

Begg, L. R.·Orriols, A. M.·Zannikou, M.·Yeh, C.·Vadlamani, P.·Kanojia, D.·Bolin, R.·Dunne, S. F.·Balakrishnan, S.·Camarda, R.·Roth, D.·Zielinski-Mozny, N. A.·Yau, C.·Vassilopoulos, A.·Huang, T.-H.·Kim, K.-Y. A.·Horiuchi, D.

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Abstract

It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.

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Begg, L. R., Orriols, A. M., Zannikou, M., Yeh, C., Vadlamani, P., Kanojia, D., Bolin, R., Dunne, S. F., Balakrishnan, S., Camarda, R., Roth, D., Zielinski-Mozny, N. A., Yau, C., Vassilopoulos, A., Huang, T.-H., Kim, K.-Y. A., Horiuchi, D.. 2023-09-23. S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition. https://doi.org/10.1101/2023.09.21.558870

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