Improving CAR-T cell immunotherapy in immunocompetent sarcoma models
Cancer immunotherapies have revolutionized how some tumor types are treated. However, evidence for their benefit in sarcoma patients remains limited with only small subsets of patients responding to treatments. Impressive results have been observed with T-cell receptor (TCR)-based adoptive T-cell therapy in synovial sarcoma. Still, not all patients respond and the development of improved adoptive T cell therapies that could potentially be applied to a wider range of sarcoma types is needed. Chimeric antigen receptor (CAR) T cells have been developed to bind directly to antigens present on the tumor cell surface. While sarcoma-associated antigens amenable to CAR-T cell treatment have emerged, CAR-T cell therapy in solid suffers from a number of hurdles, such as limited tumor infiltration or lack of efficacy. Recent efforts using genome-wide CRISPR/Cas9-based screens identified novel regulators of CAR-T cell function in other tumor types. However, most of these findings were made using in vitro assays or immunocompromised mouse models which cannot model the complex immunological signaling crosstalk that occurs in immunocompetent hosts. The tumor microenvironment (TME) harbors a variety of immunosuppressive cell types that dampen the effects of immunotherapy and can lead to an T cell exclusion phenotype or accumulation of dysfunctional T cells.