The Next Hurdle in Cancer Immunotherapy: Overcoming the Non–T-Cell–Inflamed Tumor Microenvironment

A growing body of evidence suggests that a major subset of patients with advanced solid tumors shows evidence for a T-cell-inflamed tumor microenvironment. This phenotype has positive prognostic value for several types of early stage cancer, suggesting that the attempt by the host to generate an anti-tumor immune response reflects a biologic process associated with improved patient outcomes. In metastatic disease, the presence of this phenotype appears to be associated with clinical response to several immunotherapies, including cancer vaccines, checkpoint blockade, and adoptive T-cell transfer. With the high rate of clinical response to several of these therapies, along with early data indicating that combination immunotherapies may be even more potent, it seems likely that effective immune-based therapies will become a reality for patients with a range of different cancers that physiologically support the T-cell-inflamed tumor microenvironment in a subset of individuals. Therefore, one of the next significant hurdles will be to develop new therapeutic interventions that will enable these immunotherapies to be effective in patients with the non-T-cell-inflamed phenotype. Rational development of such interventions will benefit from a detailed molecular understanding of the mechanisms that explain the presence or absence of the T-cell-inflamed tumor microenvironment, which in turn will benefit from focused interrogation of patient samples. This iterative reverse-translational research strategy has already identified new candidate therapeutic targets and approaches. It is envisioned that the end result of these investigations will be an expanded array of interventions that will broaden the fraction of patients benefitting from immunotherapies in the clinic.