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Published on: February 8, 2018
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Jesse M Zaretsky1, Angel Garcia-Diaz1, Daniel S Shin1
1From 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.).
Background:
Approximately 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.
Methods:
We 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.
Results:
Whole-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.
Conclusions:
In 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.).
Insights
Delayed melanoma relapse after anti-PD-1 therapy is linked to immune escape. Acquired resistance involves mutations in JAK1/JAK2 or B2M, impairing interferon signaling and antigen presentation.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Anti-programmed death 1 (PD-1) therapy offers durable responses in ~75% of melanoma patients.
- Delayed relapses occur long after initial tumor regression, with unknown immune escape mechanisms.
- Understanding resistance is crucial for improving long-term outcomes in melanoma immunotherapy.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to anti-PD-1 therapy in melanoma.
- To identify genetic alterations associated with disease progression after initial response.
Main Methods:
- Analysis of paired biopsy samples from baseline and relapsing lesions in four metastatic melanoma patients.
- Whole-exome sequencing to detect genetic mutations in resistant tumors.
- Assessment of interferon gamma signaling pathway and antigen presentation machinery.
Main Results:
- Clonal selection and outgrowth of resistant tumors were observed.
- Loss-of-function mutations in Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2) were found in two patients, leading to impaired interferon gamma response.
- A truncating mutation in beta-2-microglobulin (B2M) was identified in a third patient, causing loss of MHC class I expression.
Conclusions:
- Acquired resistance to PD-1 blockade in melanoma is associated with defects in interferon-receptor signaling pathways.
- Impaired antigen presentation due to B2M mutations contributes to immune escape.
- These findings elucidate key mechanisms of therapeutic resistance in melanoma immunotherapy.
