Haas et al. demonstrated that resistance to targeted therapy (TT) in melanoma leads to activation of a cancer cell–intrinsic signaling program with enhanced and altered transcriptional output associated with an immune-evasive TME and cross-resistance to immunotherapy, with implications regarding scheduling of TT and immunotherapies. The immune-evasive TME was characterized by reduced infiltration and functionality of CD103+ DCs and T cells. Inhibition of the MAPK pathway in RAFi-resistant tumors increased tumor infiltration and maturation of CD103+ DCs, reduced suppressive myeloid cells, increased T cell infiltration, and improved tumor control.
Contributed by Shishir Pant
ABSTRACT: How targeted therapies and immunotherapies shape tumors, and thereby influence subsequent therapeutic responses, is poorly understood. In the present study, we show, in melanoma patients and mouse models, that when tumors relapse after targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies. We find that cross-resistance is mediated by a cancer cell–instructed, immunosuppressive tumor microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response. Restoring the numbers and functionality of CD103+ dendritic cells can re-sensitize cross-resistant tumors to immunotherapy. Cross-resistance does not arise from selective pressure of an immune response during evolution of resistance, but from the MAPK pathway, which not only is reactivated, but also exhibits an increased transcriptional output that drives immune evasion. Our work provides mechanistic evidence for cross-resistance between two unrelated therapies, and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.
Author Info: (1) Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. (2) Department of Oncology, Lausanne University Hospital, Lausanne,
Switzerland. (3) Institute of
Author Info: (1) Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria. (2) Department of Oncology, Lausanne University Hospital, Lausanne,
Switzerland. (3) Institute of Cancer Research, London, UK. 4Institute of Molecular Biotechnology, Vienna Biocenter, Vienna, Austria. 5
Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia. 6Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia. (7) Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. (8) Molecular Modeling Group, Swiss Institute of Bioinformatics, UNIL Sorge, Lausanne, Switzerland. (9) Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. (10) Boehringer Ingelheim RCV GmBH & Co KG, Vienna, Austria. (11) Royal Prince Alfred Hospital & NSW Health Pathology, Sydney, New South Wales, Australia. (12) Royal North Shore Hospital, Sydney, New South Wales, Australia. (13) Mater Hospital, North Sydney, New South Wales, Australia. (14) MRC Cancer Unit, University of Cambridge, Cambridge, UK. (15) Department of Dermatology, Medical University of Vienna, Vienna, Austria. (16) Present address: Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria. e-mail: anna.obenauf@imp.ac.at
