The release of negative regulators of immune activation (immune checkpoints) that
limit antitumor responses has resulted in unprecedented rates of long-lasting tumor
responses in patients with a variety of cancers. This can be achieved by antibodies
blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1)
pathway, either alone or in combination. The main premise for inducing an immune response
is the pre-existence of antitumor T cells that were limited by specific immune checkpoints.
Most patients who have tumor responses maintain long lasting disease control, yet
one third of patients relapse. Mechanisms of acquired resistance are currently poorly
understood, but evidence points to alterations that converge on the antigen presentation
and interferon gamma signaling pathways. New generation combinatorial therapies may
overcome resistance mechanisms to immune checkpoint therapy.