Pulmonary resection after immunotherapy

Abstract

The past decade has shown considerable promise in immune-checkpoint blockade as a means of augmenting antitumor immunity, placing immunotherapy alongside traditional modalities as a pillar of cancer treatment. Current checkpoint-blockade strategies are centered either on cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) or programmed cell death protein-1 pathway (PD-1/PD-L1) (1).CTLA-4 and PD-1 facilitate T-cell attenuation at different stages of the T-cell response. Immediately following T-cell receptor ligation, CTLA-4 is translocated to the T-cell surface, where it competes for binding to CD80 and CD86, ligands that could otherwise provide positive co-stimulation to the T-cell via CD-28 (2). As a result, CTLA-4 increases the activation threshold of T cells, impeding antitumor immunity by dampening the sensitivity of T-cells to self and tumor antigens (3). The PD-1 pathway, by contrast, is induced later during T cell activation, attenuating TCR signaling following binding by PD-L1. Cancer cells expressing PD-L1 are thereby able to evade immune detection, while tumor-infiltrating immune cells can themselves express PD-L1 in response to cytokines such as . PD-L1 expression throughout the inflammatory tumor microenvironment can therefore lead to PD-1-mediated T-cell exhaustion (2).Whereas anti-CTLA-4 monoclonal antibody therapy has earned FDA-approval for treating advanced melanoma, CTLA-4 blockade has shown minimal activity in the treatment of non-small cell lung cancer (NSCLC). Meanwhile, agents targeting the PD-1/PD-L1 axis have shown considerable efficacy in treating advanced NSCLC (4). Currently, there is significant interest in determining the therapeutic potential of combined CTLA-4 and PD-1 blockade. In CheckMate 227, a randomized, open-label, phase 3 trial by Hellman et al. first-line treatment of stage IV or recurrent NSCLC with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) resulted in a longer duration of overall survival than did chemotherapy (5).