Therapeutic Implications of Natural Killer Cell Immune Surveillance in Lung Cancer

JI Program: Pulmonary


Lung cancer is the leading cause of cancer mortality worldwide. Use of immune-checkpoint blockers has yielded impressive clinical benefit, but only in a subset of patients. Recent studies demonstrate that the expression of the checkpoint-ligands like PDL-1 on host cells, rather than on cancer cells, determines the efficacy of checkpoint-blockade in mice. A number of host immune cells, including NK cells, express PDL-1 and could dictate the efficacy of checkpoint-inhibitors in humans. A recent phase I/II study combining anti-KIR (an inhibitory

NK cell receptor) antibody with anti-PD1 antibody in head & neck cancer showed a dramatic 24% objective response rate over 13.3% with anti-PD1 alone. Epithelialmesenchymal                transition (EMT) is a transdifferentiation process by which epithelial cancer cells acquire migratory and invasive capabilities to metastasize. We demonstrated that a 20-gene EMT-signature is predictive of survival in non-small cell lung cancer (NSCLC) patients. More recently, we showed that EMT-induced expression of a cell-adhesion molecule CADM1 renders cancer cells more susceptible to NK cytotoxicity and inhibits metastasis. This proposal will test whether boosting NK cell functions can control metastasis and whether the EMT signature can be predictive of anti-tumor efficacy of NK cell therapy, as well as response to checkpoint-blockade therapy in NSCLC. These studies will provide proof-of- principle for a potential phase I/II study for proposed NK cell-based strategies, along with the support to the potential of EMT-signature and NK cell phenotype in predicting response to checkpoint-blockade and pave the way for subsequent mechanistic studies.