208P - Targeting pro-tumor TAMs to improve immune checkpoint response of advanced bladder cancer

Background

Bladder cancer (BC) represents the fourth most common cancer in men with a poor patient prognosis for advanced disease. The poor survival of these muscle-invasive bladder cancer (MIBC) patients emphasizes the obvious need to improve their therapies. Checkpoint inhibitors that block the PD-1/PD-L1 axis were successfully introduced in routine medicine. However, only 15=25% of patients with MIBC respond to this treatment. Understanding why MIBC do not respond to these treatments and developing new therapeutic strategies are urgently needed.

Methods

Using an anti-PD1-resistant mouse model of BC already developed in the lab, we characterized tumor-associated macrophage (TAMs) evolution over tumor progression.

Results

We identified a subset of pro-tumor TAMs that expressed CXCR4 which increased in advanced stages. Data on human MIBC samples confirmed the presence of CXCR4⁺ macrophages in the tumor core and the increase of its ligand in the serum of patients compared to healthy donors. Interestingly, upon administration of a CXCR4 inhibitor, we strongly reduced macrophage number within the tumor and significantly prolonged mice survival. Combining the CXCR4 inhibitor with immunotherapy increased the survival of MIBC-bearing mice.

Conclusions

Thanks to study of a pre-clinical model recapitulating the human disease and study in patients, we selected the CXCR4/CXCL12 pathway as a promising target to decrease pro-tumor macrophages in MIBC and to improve therapeutic management.

Legal entity responsible for the study

The authors.

Funding

Swiss Cancer Research foundation ISREC Foundation.

Disclosure

All authors have declared no conflicts of interest.