The infiltration of myeloid cells helps tumors to overcome immune surveillance 
and imparts resistance to cancer immunotherapy. Thus, strategies to modulate the 
effects of these immune cells may offer a potential therapeutic benefit. We 
report here that tasquinimod, a novel immunotherapy which targets S100A9 
signaling, reduces the immunosuppressive properties of myeloid cells in 
preclinical models of bladder cancer (BCa). As single anticancer agent, 
tasquinimod treatment was effective in preventing early stage tumor growth, but 
did not achieve a clear antitumor effect in advanced tumors. Investigations of 
this response revealed that tasquinimod induces an increase in the expression of 
a negative regulator of T cell activation, Programmed-death-ligand 1 (PD-L1). 
This markedly weakens its antitumor immunity, yet provokes an "inflamed" milieu 
rendering tumors more prone to T cell-mediated immune attack by PD-L1 blockade. 
Interestingly, the combination of tasquinimod with an Anti-PD-L1 antibody 
enhanced the antitumor immune response in bladder tumors. This combination 
synergistically modulated tumor-infiltrating myeloid cells, thereby strongly 
affecting proliferation and activation of effector T cells. Together, our data 
provide insight into the rational combination of therapies that activate both 
innate and adaptive immune system, such as the association of S100A9-targeting 
agents with immune checkpoints inhibitors, to improve the response to cancer 
immunotherapeutic agents in BCa.