Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma

109Citations
Citations of this article
100Readers
Mendeley users who have this article in their library.

Abstract

Background: While cancer immunotherapies including checkpoint blockade antibodies, adoptive T cell therapy, and even some vaccines have given rise to major clinical responses with durability in many cases, a subset of patients who initially respond subsequently develop secondary resistance to therapy. Tumor-intrinsic mechanisms of acquired immunotherapy resistance are incompletely understood. Methods: Baseline and treatment-resistant tumors underwent molecular analysis via transcriptional profiling or genomic sequencing for oncogenic alterations and histologic analysis for T cell infiltration to investigate mechanisms contributing to T cell exclusion and acquired resistance to immunotherapy. Results: We describe two patients with metastatic melanoma who initially showed a durable partial response to either a melanoma-peptide/interleukin-12 vaccine or combined anti-CTLA-4 + anti-PD-1 therapy, but subsequently developed new treatment-resistant metastases. In the first case, the recurrent tumor showed new robust tumor expression of β-catenin, whereas in the second case genomic sequencing revealed acquired PTEN loss. Both cases were associated with loss of T cell infiltration, and both pathways have been mechanistically linked to immune resistance preclinically. Conclusion: Our results suggest that secondary resistance to immunotherapies can arise upon selection for new oncogenic variants that mediate T cell exclusion. To identify the spectrum of underlying mechanisms of therapeutic resistance, similar evaluation for the emergence of tumor-intrinsic alterations in resistant lesions should be done prospectively at the time of relapse in a range of additional patients developing secondary resistance.

Cite

CITATION STYLE

APA

Trujillo, J. A., Luke, J. J., Zha, Y., Segal, J. P., Ritterhouse, L. L., Spranger, S., … Gajewski, T. F. (2019). Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma. Journal for ImmunoTherapy of Cancer, 7(1). https://doi.org/10.1186/s40425-019-0780-0

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free