Kellie B Haworth1,2, Michael A Arnold3,4, Christopher R Pierson3,4,5, Jennifer L Leddon2,6,7, Dias K Kurmashev8, Hayley M Swain2, Brian J Hutzen2, Ryan D Roberts1,2, Timothy P Cripe1,2. 1. Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio. 2. Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. 3. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio. 4. Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio. 5. Division of Anatomy, The Ohio State University, Columbus, Ohio. 6. Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. 7. Immunobiology Graduate Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. 8. Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.
Abstract
BACKGROUND: Over 10,000 US children are diagnosed with cancer yearly. Though outcomes have improved by optimizing conventional therapies, recent immunotherapeutic successes in adult cancers are emerging. Cytotoxic T lymphocytes (CTLs) are the primary executioners of adaptive antitumor immunity and require antigenic presentation in the context of major histocompatibility complex (MHC) class I and the associated β-2-microglobulin (B2M). Loss of MHC I expression is a common immune escape mechanism in adult malignancies, but pediatric cancers have not been thoroughly characterized. The essential nature of MHC I expression in CTL-mediated cell death may dictate the success of immunotherapies, which rely on eliciting an adaptive response. PROCEDURE: We queried pediatric tumor microarray databases for MHC I and B2M gene expression. We detected MHC I in pediatric tumor cell lines by flow cytometry and characterized MHC I and B2M expression in patient samples by immunohistochemistry. To determine whether therapeutic approaches might enhance MHC I expression in selected models in vitro, we tested effects of exposure to IFN-γ and histone deacetylase inhibitors. RESULTS: Pediatric tumors overall, as well as samples within select individual tumor subtypes, exhibit wide ranges of MHC I and B2M gene and protein expression. For most cell lines tested, MHC I was inducible in vitro. CONCLUSIONS: MHC I and B2M expression vary among pediatric tumor types and should be evaluated as potential biomarkers, which might identify patients most likely to benefit from MHC I dependent immunotherapies. Modulation of MHC I expression may be a promising mechanism for enhancing MHC I dependent immunotherapeutic efficacy.
BACKGROUND: Over 10,000 US children are diagnosed with cancer yearly. Though outcomes have improved by optimizing conventional therapies, recent immunotherapeutic successes in adult cancers are emerging. Cytotoxic T lymphocytes (CTLs) are the primary executioners of adaptive antitumor immunity and require antigenic presentation in the context of major histocompatibility complex (MHC) class I and the associated β-2-microglobulin (B2M). Loss of MHC I expression is a common immune escape mechanism in adult malignancies, but pediatric cancers have not been thoroughly characterized. The essential nature of MHC I expression in CTL-mediated cell death may dictate the success of immunotherapies, which rely on eliciting an adaptive response. PROCEDURE: We queried pediatric tumor microarray databases for MHC I and B2M gene expression. We detected MHC I in pediatric tumor cell lines by flow cytometry and characterized MHC I and B2M expression in patient samples by immunohistochemistry. To determine whether therapeutic approaches might enhance MHC I expression in selected models in vitro, we tested effects of exposure to IFN-γ and histone deacetylase inhibitors. RESULTS:Pediatric tumors overall, as well as samples within select individual tumor subtypes, exhibit wide ranges of MHC I and B2M gene and protein expression. For most cell lines tested, MHC I was inducible in vitro. CONCLUSIONS: MHC I and B2M expression vary among pediatric tumor types and should be evaluated as potential biomarkers, which might identify patients most likely to benefit from MHC I dependent immunotherapies. Modulation of MHC I expression may be a promising mechanism for enhancing MHC I dependent immunotherapeutic efficacy.
Authors: Kellie B Haworth; Michael A Arnold; Christopher R Pierson; Kwangmin Choi; Nicholas D Yeager; Nancy Ratner; Ryan D Roberts; Jonathan L Finlay; Timothy P Cripe Journal: Oncotarget Date: 2017-05-30