[en] Immunotherapy has reshaped cancer treatment over the last decade. However, for the majority of cancers, only a limited subset of patients experience long-lasting response. Triple-negative breast cancer (TNBC) represents 10-20% of invasive breast cancers and is particularly aggressive. Immunotherapy, in the form of PD-1 blockade, has recently been added to its treatment arsenal. Undoubtedly, the blockade of novel “second generation” immune checkpoints could be promising to enhance the number of responders.
This project aims at highlighting new immune checkpoints of particular interest in the context of TNBC and studying the impact of their inhibition on TNBC progression. To this end, we selected potential immune checkpoints that showed high mRNA expression in TNBC using bioinformatic analyses. Next, we chose the targets displaying a higher protein expression in TNBC compared to the 3 other categories of breast cancer (LumA, LumB and HER2+) by using immunohistochemistry.
The proteins VISTA, sirp-α, CD47 and PVR were selected. Several murine syngeneic tumor models were considered and checkpoint expression was thoroughly investigated in specific immune populations. Monoclonal antibodies targeting the immune checkpoints of interest were selected and their effect on tumor growth as well as on the intratumoral composition of the immune cell landscape was assessed.
We showed that tumor growth was significantly slowed down in Balb/C mice bearing 4T1 tumors treated with the anti-VISTA, anti-CD47 and anti-TIGIT (PVR ligand) antibodies, while no effect was shown in a comparable NOD-Scid model. We chose to focus our research on the blockade of VISTA, which was proven effective in two additional TNBC models (67NR and E0771). By analyzing the immune cells part of the tumor microenvironment, we found that the blockade of VISTA was associated with a decrease in the proportion of regulatory T cells, both CD4+ and CD8+ and a favorable increase of the M1-like/M2-like macrophages ratio. Changes in the activation of infiltrating immune cells have also been highlighted.
Overall, our findings suggest an association between the blockade of the immune checkpoint VISTA and the remodelling of the immune tumor microenvironment, which correlates with a significant tumor growth reduction in various syngeneic breast cancer models.
