Resistance to anticancer immunity in cancer patients: potential strategies to reverse resistance

In the 1990s, the application of immunotherapy approaches to target cancer cells resulted in significant clinical responses in patients with advanced malignancies who were refractory to conventional therapies. While early immunotherapeutics were focused on T cell-mediated cytotoxic activity, subsequent efforts were centered on targeted antibody-mediated anticancer therapy. The initial success with antibody therapy encouraged further studies and, consequently, there are now more than 25 FDA-approved antibodies directed against a range of targets. Although both T cell and antibody therapies continue to result in significant clinical responses with minimal toxicity, a significant subset of patients does not respond to immunotherapy and another subset develops resistance following an initial response. This review is focused on describing examples showing that cancer resistance to immunotherapies indeed occurs. In addition, it reviews the mechanisms being used to overcome the resistance to immunotherapies by targeting the tumor cell directly and/or the tumor microenvironment.