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Sequential Immune Escape and Shifting of T Cell Responses in a Long-Term Survivor of Melanoma ¹

Galina V. Yamshchikov^*, David W. Mullins, Chien-Chung Chang^¶, Takeshi Ogino^¶, Lee Thompson^*, Jennifer Presley^*, Holly Galavotti^*, William Aquila^*, Donna Deacon^*, William Ross, James W. Patterson, Victor H. Engelhard, Soldano Ferrone^¶ and Craig L. Slingluff, Jr^2,*

^* Department of Surgery, Department of Microbiology and Beirne B. Carter Center for Immunology Research, Department of Pathology, and Cancer Center FACS Core Facility, University of Virginia, Charlottesville, VA 22908; and^¶ Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

Immune-mediated control of tumors may occur, in part, through lysis of malignant cells by CD8⁺ T cells that recognize specific Ag-HLA class I complexes. However, tumor cell populations may escape T cell responses by immune editing, by preventing formation of those Ag-HLA complexes. It remains unclear whether the human immune system can respond to immune editing and recognize newly arising escape variants. We report an example of shifting immune responses to escape variants in a patient with sequential metastases of melanoma and long-term survival after surgery alone. Tumor cells in the first metastasis escaped immune recognition via selective loss of an HLA haplotype (HLA-A11, -B44, and -Cw17), but maintained expression of HLA-A2. In the second metastasis, immune escape from an immunodominant MART-1-specific T cell response was mediated by HLA class I down-regulation, resulting in a failure to present this epitope, but persistent presentation of a tyrosinase-derived epitope. Consequent to this modification in tumor Ag presentation, the dominant CTL response shifted principally toward a tyrosinase-targeted response, even though tyrosinase-specific CTL had been undetectable during the initial metastatic event. Thus, in response to immune editing of tumor cells, a patient’s spontaneous T cell response adapted, gaining the ability to recognize and to lyse "edited" tumor targets. The observation of both immune editing and immune adaptation in a patient with long-term survival after surgery alone demonstrates an example of immune system reactivity to counteract the escape mechanism(s) developed by tumor cells, which may contribute to the clinical outcome of malignant disease.

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