Abstract A43: Immunologic profiling of pediatric malignancies for plausible immunotherapeutic trial selection
Authors: Haworth Kellie B. , Leddon Jennifer L. , Chen Chun-Yu , Cripe Timothy P. 
Published: October 2015

Although clinical trials have resulted in significant improvement in the treatment of childhood cancers, further progress using more targeted and less toxic modalities requires a better understanding of the biology of these diseases, including how they develop the ability to overcome rejection by the immune system. In adult cancers, immunotherapies are gaining traction with increasing reports of antitumor efficacy. Cytotoxic T lymphocytes (CTLs) have a major role in the immune response to tumors and require antigenic presentation in the context of Major Histocompatibility Complex (MHC) Class I. Studies have reported the degree of these tumor-infiltrating lymphocytes to be directly correlated with prognosis. Prior studies have also shown that MHC Class I is down-regulated in 40-90% of adult cancer cases, making them resistant to an immune attack by CTLs, and have indicated that MHC Class I expression down-regulation is associated with poorer prognosis. Some immunotherapeutic approaches, such as chimeric antigen receptors and bi-specific antibodies, are MHC Class I-independent. Others, such as vaccines and the adoptive transfer of tumor-specific T-cells, depend upon antigenic peptide presentation by MHC Class I to be effective. In addition to direct oncolysis, oncolytic viruses exert their therapeutic effects in part by inducing a T-cell response against tumor-associated antigens, rendering their benefits to be also somewhat MHC-dependent. Oncolytic herpes simplex virus (oHSV) therapy is an emerging immunotherapeutic platform in clinical trials, and our lab has previously characterized implantable mouse RMS tumor cell lines for their suitability as immunocompetent models for the study of the adaptive immune response to oHSV therapy. For the appropriate enrollment of patients onto immunotherapeutic clinical trials, it is imperative to know the MHC Class I expression on tumor cells, and, for virotherapy, the effects of infection on its expression. We sought to characterize MHC Class I expression in pediatric malignancies and queried mRNA microarray databases including clinical and preclinical datasets. We characterized the immunologic profile of pediatric malignancies through the identification of tumor types which exhibit MHC Class I and the associated β-2-microglobulin molecule expression. Preliminary data suggest that sarcomas, including Ewing sarcoma, osteosarcoma, and both embryonal and alveolar rhabdomyosarcomas (RMS), Wilms' tumors, and some brain tumors, such as atypical teratoid/ rhabdoid tumors (AT/RT) and ependymomas, exhibit decreased MHC Class I mRNA levels relative to other cancer types. We discovered that MHC Class I can be up-regulated in vitro in many human pediatric cancer cell lines, indicating a reversible epigenetic mechanism for down-regulation. Our immunocompetent murine RMS models suggest that the oHSV in vivo therapeutic effect is largely T-cell dependent. The most resistant model exhibited a cellular infiltrate dominated by CD4+ T cells, while the sensitive model demonstrated higher baseline CD8+ T cells. In fact, the best therapeutic response, including complete tumor rejection and resistance to tumor re-challenge, correlated with highest CTL infiltrate and the highest MHC Class I expression. These data support the likelihood that the oHSV therapeutic effect is not necessarily governed by susceptibility or permissiveness to oHSV oncolysis, but rather by the effect of oHSV on tumor cell-microenvironmental immunologic interactions. We hypothesize that MHC Class I status may serve as an important biomarker for patient inclusion in therapeutic trials of MHC-dependent immunotherapies such as oncolytic viral therapy, and modulation of MHC Class I expression will be a promising strategy to enhance immunotherapeutic efficacy.

Citation Format: Kellie B. Haworth, Jennifer L. Leddon, Chun-Yu Chen, Timothy P. Cripe. Immunologic profiling of pediatric malignancies for plausible immunotherapeutic trial selection. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A43.