The Cellular Tumor Immune Microenvironment of Childhood Solid Cancers: Informing More Effective Immunotherapies

SIMPLE SUMMARY: Cellular immunotherapy has emerged as a novel treatment modality of cancer but is largely inefficient in solid cancers of childhood and adolescence. Besides tumor cells, solid cancers contain various bystander cell populations that can suppress immune responses and prevent the action of therapeutic effector cells within the tumor niche. This review summarizes current insights into the types of cells with an immunosuppressive function in the cellular microenvironment of common childhood cancers, along with novel approaches to overcome these barriers to enable effective immunotherapies. ABSTRACT: Common pediatric solid cancers fail to respond to standard immuno-oncology agents relying on preexisting adaptive antitumor immune responses. The adoptive transfer of tumor-antigen specific T cells, such as CAR-gene modified T cells, is an attractive strategy, but its efficacy has been limited. Evidence is accumulating that local barriers in the tumor microenvironment prevent the infiltration of T cells and impede therapeutic immune responses. A thorough understanding of the components of the functional compartment of the tumor microenvironment and their interaction could inform effective combination therapies and novel engineered therapeutics, driving immunotherapy towards its full potential in pediatric patients. This review summarizes current knowledge on the cellular composition and significance of the tumor microenvironment in common extracranial solid cancers of childhood and adolescence, such as embryonal tumors and bone and soft tissue sarcomas, with a focus on myeloid cell populations that are often present in abundance in these tumors. Strategies to (co)target immunosuppressive myeloid cell populations with pharmacological anticancer agents and with selective antagonists are presented, as well as novel concepts aiming to employ myeloid cells to cooperate with antitumor T cell responses.