Tucatinib promotes immune activation and synergises with PD-1/PD-L1 inhibition in HER2-positive breast cancer
Menée à l'aide de modèles murins de cancer mammaire HER2+, cette étude met en évidence l'intérêt du tucatinib pour améliorer la réponse antitumorale des cellules immunitaires et démontre les effets synergiques de cet inhibiteur de tyrosine kinase et des anti-PD-1/PD-L1
PD-1 and PD-L1 inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.We investigated the anti-tumor efficacy and contribution of the immune response of tucatinib using two immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1/PD-L1 checkpoint inhibitors.In both models, tucatinib significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of TILs in mice treated with tucatinib showed increased frequency, higher proliferation and enhanced effector function of CD8+ effector memory T cells (TEM). Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ NK cells, monocytes, and MHC II expression on dendritic cells and macrophages, and a decrease in myeloid derived suppressor cells. Gene expression analysis revealed significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response and antigen receptor signalling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated significantly increased efficacy and improved survival of mice compared with tucatinib alone.Tucatinib modulates the immune microenvironment favourably and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.