• Jesse M Zaretsky, Angel Garcia-Diaz, Daniel S Shin, Helena Escuin-Ordinas, Willy Hugo, Siwen Hu-Lieskovan, Davis Y Torrejon, Gabriel Abril-Rodriguez, Salemiz Sandoval, Lucas Barthly, Justin Saco, Blanca Homet Moreno, Riccardo Mezzadra, Bartosz Chmielowski, Kathleen Ruchalski, I Peter Shintaku, Phillip J Sanchez, Cristina Puig-Saus, Grace Cherry, Elizabeth Seja, Xiangju Kong, Jia Pang, Beata Berent-Maoz, Begoña Comin-Anduix, Thomas G Graeber, Paul C Tumeh, Ton N M Schumacher, Roger S Lo, and Antoni Ribas.
• From the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).
• N. Engl. J. Med. 2016 Sep 1; 375 (9): 819-29.

BackgroundApproximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.MethodsWe analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.ResultsWhole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.ConclusionsIn this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

35 keywords...

hide…