Integrin blocking peptide reverses immunosuppression in experimental gliomas and improves anti-PD-1 therapy outcome

Abstract

ABSTRACTImmune checkpoint inhibitors (ICI) presented clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. Lack of ICI efficacy in GBM is attributed to the accumulation of immunosuppressive myeloid cells that create the “cold” tumor microenvironment (TME) impeding infiltration and activation of effector T cells. We developed a designer RGD peptide that hindered glioma-instigated, integrin-mediated pro-tumoral reprogramming of myeloid cells and blocked microglia-dependent invasion of human and mouse glioma cells in co-culturesin vitro. Intratumorally-delivered RGD alone did not reduce glioma growth in syngeneic mice but prevented the emergence of immunosuppressive myeloid cells and led to peritumoral blood vessels normalization. Furthermore, combining RGD with immunotherapy using PD-1 blockade reduced tumor growth, led to upsurge of proliferating, interferon-ɣ producing CD8+T cells and depleted regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, consistently with the restored “hot” inflammatory TME and boosted immunotherapy responses. RGD modified the phenotypes of myeloid cells in human gliomas in nude mice. Thus, combining the integrin blockade with ICI reinvigorates antitumor immunity and paves the way to improve immunotherapy outcomes in GBM.