Adaptive T lymphocyte immunity against tumor neoantigens is the goal of many cancer immunotherapies. Components of the innate immune system are required to facilitate this response, but can also hinder immunotherapeutic strategies. Consequently, there is increasing evidence that the efficacy of therapeutics promoting T lymphocyte effector functions can be enhanced by concurrent modulation of innate immune cell functions. For example, some therapeutic strategies that target innate immune cell functions include: the promotion of dendritic cell recruitment and activation; depletion or inhibition of myeloid-derived suppressor cells (MDSCs) and M2-type macrophages; improvement in the pro-inflammatory cytokine and chemokine milieu; and suppression of inhibitory cytokines and enzymes. Modulation of innate immune system components in this way can help create an immunologically “hot” tumor microenvironment that facilitates T lymphocyte maturation, from antigen priming to effector function.

Ongoing studies by our group suggest that some osteosarcoma cells are defective in their ability to induce inflammation in response to genomic instability and DNA damage. This deficiency arises due to decreased expression of stimulator of interferon genes (STING) in some cell lines. STING typically functions to link the detection of cytoplasmic DNA with induction of type I interferon and chemokine expression, which is critical for recruitment and activation of effector cells. While STING signaling appears crucial for the development of radiation-induced systemic anti-cancer immunity (i.e., the abscopal effect) in some models, deficiencies in STING expression also predispose cancer cells to enhanced susceptibility to oncolytic DNA viruses. Therefore, understanding how tumor cells dampen or promote components of the host innate immune system will improve our ability to create rational immunotherapeutic combinations.