The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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Haas, L., Elewaut, A., Gerard, C.L. et al. Nat Cancer 2, 693–708 (2021).
“This article shows the importance of preclinical studies to identify the best combination strategy of targeted and immuno-therapies.”
EACR Board
Summary of the findings
The combination (or sequential application) of different cancer therapies represents a powerful opportunity to increase response and cure rates for cancer patients. However, how cancer cells and the crosstalk within the tumor microenvironment change upon different therapeutic challenges, and how this might influence the outcome of subsequent therapies is poorly understood.
In this study we show 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 found 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. We showed that cross-resistance is controlled by a reactivated and rewired MAPK signaling pathway, which not only restores its cancer cell-intrinsic oncogenic functions but, in addition, drives an immune-evasive gene expression program that establishes a completely different immune phenotype conferring resistance to immunotherapy. Importantly, this rewired state not only dominates RAFi and RAFi/MEKi-resistant tumors but is already present in a subset of therapy-naïve tumors that respond poorly to immunotherapy. 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.
Future impact of the findings
Currently, more than half of BRAF-mutant patients initially receive targeted therapy, often until they acquire resistance. Our data, together with other work and data from prospective phase III clinical trials e.g. DREAMseq/NCT02224781, provide a strong scientific rationale for using immunotherapy as a first-line treatment. The concept of targeted-therapy/immunotherapy cross-resistance in BRAF-mutant melanoma may also extend to other tumor types and therapies, which should be evaluated. Collectively, our work highlights the importance of understanding the complex and dynamic biology of cancer cells and the tumor microenvironment in all three phases of therapy, i.e., the therapy-naïve, the responding/adapting, and the therapy-resistant state in order to guide the rational combination and optimal sequence of therapies.
