Overcoming immune suppression in the tumor microenvironment: Implications for multi-modal therapy

Effective immunotherapy, whether by checkpoint blockade, vaccines or adoptive cell therapy, is limited in most patients by a fundamental barrier: the immunosuppressive tumor microenvironment. This problem is more than just the suppression of effector T cells, but also includes profound defects in the inflammatory milieu and immunogenic antigen-presenting cells that are required to drive T cell activation. To date, much of the field of immunotherapy has focused on downstream checkpoints that regulate activated T cells, or on vaccination and T cell adoptive transfer to expand the T cell pool. Relatively less attention has been given to regulatory pathways that govern cross-presentation and response to endogenous tumor antigens. But these “upstream” pathways become particularly important in settings where immunotherapy is combined with standard-of-care chemotherapy or radiation therapy, both of which release a wave of tumor antigens. The choice of whether to treat these antigens as tolerizing or immunizing is fundamental to generating an effective immune response against the tumor. In this chapter we consider immunosuppressive mechanisms in the tumor microenvironment from the perspective of factors that that may impact the response to antigens from dying tumor cells.