Increasing tumor-infiltrating T cells through inhibition of CXCL12 with NOX-A12 synergizes with PD-1 blockade
Menée sur des sphéroïdes de cellules tumorales et stromales mimant une tumeur solide et menée à l'aide d'un modèle murin de cancer colorectal, cette étude montre que le blocage de la chimiokine CXCL12 par l'aptamère L-RNA NOX-A12 et l'inhibition du point de contrôle immunitaire PD-1 par un traitement anti-PD1 augmentent de façon synergique l'infiltration des lymphocytes T dans la tumeur
Immune checkpoint inhibitors promote T cell-mediated killing of cancer cells, however only a subset of patients benefit from the treatment. A possible reason for this limitation may be that the tumor microenvironment (TME) is immune privileged, which may exclude cytotoxic T cells from the vicinity of cancer cells. The chemokine CXCL12 is key to the TME-driven immune suppression. In this study we investigated the potential of CXCL12 inhibition by use of the clinical-stage L-RNA-aptamer NOX-A12 (olaptesed pegol) to increase the number of tumor-infiltrating lymphocytes. We used heterotypic tumor-stroma spheroids that mimic a solid tumor with a CXCL12-abundant TME. NOX-A12 enhanced the infiltration of T and NK cells in a dose-dependent manner. NOX-A12 and PD-1 checkpoint inhibition synergistically activated T cells in the spheroids, indicating that the agents complement each other. The findings were validated in vivo in a syngeneic murine model of colorectal cancer in which the addition of NOX-A12 improved anti-PD-1 therapy. Taken together, our work shows that CXCL12 inhibition can break the immune-privileged status of the TME by paving the way for immune effector cells to enter into the tumor, thereby broadening the applicability of checkpoint inhibitors in cancer patients.