Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: Implications for immunotherapy
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Kellie B. Haworth1,2, Michael A. Arnold3,4, Christopher R. Pierson3,4,5, Kwangmin Choi6, Nicholas D. Yeager1, Nancy Ratner6, Ryan D. Roberts1,2, Jonathan L. Finlay1 and Timothy P. Cripe1,2
1Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA
2Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
3Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA
4Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio, USA
5Division of Anatomy, Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio, USA
6Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
Kellie B. Haworth, email: [email protected]
Keywords: NF1, MPNST, neurofibromas, immunotherapy, immunophenotype
Received: December 14, 2016 Accepted: April 16, 2017 Published: May 30, 2017
Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, β-2-microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4+, CD8+, FOXP3+, CD56+, and CD45RO+ lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach.
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