Targeted therapies and immunotherapies represent main pillars of cancer treatment, yet how they shape tumours during treatment response and resistance and thereby influence subsequent therapeutic responses is poorly understood. Here, we show in melanoma patients and mouse models that when tumours relapse on targeted MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite their entirely different mode of action. We find that cross-resistance is mediated via a cancer cell-instructed, immune-suppressive tumour microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response. Restoration of CD103+ dendritic cell numbers and functionality can re-sensitize cross-resistant tumours to immunotherapy. Using our lineage tracing method CaTCH, which allows the retrospective isolation of founding clones prior to evolutionary selection, we demonstrate that cross-resistance is acquired during MAPKi treatment. Cross-resistance does not arise from the selective pressure of an immune response during the evolution of resistance, paradoxically it results from the MAPK pathway, which is not only reactivated during the formation of targeted therapy resistance but has gained increased transcriptional output driving immune evasion. Our work provides mechanistic evidence for cross-resistance between unrelated therapies and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.

Citation Format: Anna C. Obenauf. What does not kill it makes it stronger: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA20.