Modulating the tumor microenvironment improves antitumor effect of anti-PD-L1 mAb in breast cancer.

Introduction: Immune checkpoint inhibitors (ICIs) have provided noteworthy benefits in multiple cancer patients. However, the efficacy of monotherapy of ICIs was very limited. In this study, we endeavored to explore whether losartan can modulate the solid tumor microenvironment (TME) and improve the therapeutic efficacy of anti-PD-L1 mAb in 4T1 mouse breast tumor model and the underlying mechanism. Methods: The tumor-bearing mice were treated with control agents, losartan, anti-PD-L1 mAb or the dual agents. The blood and tumor tissues were respectively used for ELISA and immunohistochemical analysis. CD8-depletion and lung metastatic experiments were performed. Results: Compared to control group, losartan inhibited the expression of alpha-smooth muscle actin (α-SMA), deposition of collagen I in the tumor tissues. The concentration of transforming growth factor-β1 (TGF-β1) in the serum was low in the losartan treated group. Although losartan alone was ineffective, the combination of losartan and anti-PD-L1 mAb elicited dramatic antitumor effect. Immunohistochemical analysis revealed that there were more intra-tumoral infiltration of CD8⁺ T cells and increased granzyme B production in the combination therapy group. In addition, the size of spleen was smaller in the combination therapy group, compared to monotherapy. The CD8-depleting Abs abrogated the antitumor efficacy of losartan and anti-PD-L1 mAb in vivo. The combination of losartan and anti-PD-L1 mAb significantly inhibited 4T1 tumor cells lung metastatic in vivo. Conclusion: Our results indicated that losartan can modulate the tumor microenvironment, and improve the efficacy of anti-PD-L1 mAb.