American Association for Cancer Research
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Supplementary Figure Legends from Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency

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posted on 2023-03-31, 00:25 authored by Fang Zhao, Antje Sucker, Susanne Horn, Christina Heeke, Nicola Bielefeld, Barbara Schrörs, Anne Bicker, Monika Lindemann, Alexander Roesch, Gustav Gaudernack, Mathias Stiller, Jürgen C. Becker, Volker Lennerz, Thomas Wölfel, Dirk Schadendorf, Klaus Griewank, Annette Paschen

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Hiege Stiftung gegen Hautkrebs

Stiftung Rheinland-Pfalz für Innovation

Deutsche Krebshilfe

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ARTICLE ABSTRACT

Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8+ T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Junhigh/MITFlow phenotype, possibly associated with immunosuppression, which contrasted with a c-Junlow/MITFhigh phenotype of T cell–edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347–58. ©2016 AACR.

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