Role of immunotherapy in Ewing sarcoma

Abstract

Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer-testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.

Keywords: adoptive; chimeric antigen; immunotherapy; receptors; t-lymphocytes; vaccination.

Figure 1

Immunosuppression in the Ewing sarcoma tumor microenvironment. Low expression of human leukocyte antigen (HLA)-A, B, C on Ewing sarcoma cells prevents recognition of tumor-associated antigens by antigen presenting cells and effector T cells, while high expression of HLA-G actively suppresses tumor-specific T cells. Tregs also function to dampen the antitumoral T cell response, namely through production of suppressive cytokines and binding of CD80 on antigen presenting cells (APCs). The binding of CD80 on APCs by Treg CTLA-4 prevents CD80-CD28 costimulation of T cells, resulting in T cell anergy. The presence and activity of intratumural Tregs is further augmented by cytokines produced by F2 fibrocytes and myeloid-derived suppressor cells (MDSCs). Similarly to Tregs, F2 fibrocytes and other MDSCs also produce cytokines that dampen the cytotoxic T cell response. HLA, human leukocyte antigen; TCR, T cell receptor; Tregs, regulatory T cells.

Figure 2

Targets for cancer immunotherapies in Ewing sarcoma. Extracellular targets are natively expressed on the surface of Ewing sarcoma cells and can be targeted by both cellular and non-cellular immunotherapies. These therapies include CAR T cells, monoclonal antibodies (mAbs) and bispecific T cell engagers. In contrast, intracellular targets require presentation of naturally processed peptides in an HLA context and cellular immunotherapies such as transgenic T cell receptor (TCR) T cells, cancer vaccine or autologous tumor-infiltrating lymphocytes. CAR, chimeric antigen receptor; TCR, T cell receptor.