Lung cancer cells have developed strategies to become invisible to the immune system, which would otherwise recognize and eliminate the tumor. Recent studies have shown that one of the most important immune evasion mechanisms is the activation of a protein on the surface of lung cancer cells called PD-L1, for Programmed Death Ligand 1. PD-L1 binds to PD-1 on the surface of immune cells, sending a signal to shut off the immune response. Immunotherapy is a cancer treatment strategy in which the mechanisms through which tumor cells block the immune system are shut off, triggering anti-tumor immune reactions. Clinical trials using immunotherapy drugs that block the binding of the PD-1 receptor t...

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Lung cancer cells have developed strategies to become invisible to the immune system, which would otherwise recognize and eliminate the tumor. Recent studies have shown that one of the most important immune evasion mechanisms is the activation of a protein on the surface of lung cancer cells called PD-L1, for Programmed Death Ligand 1. PD-L1 binds to PD-1 on the surface of immune cells, sending a signal to shut off the immune response. Immunotherapy is a cancer treatment strategy in which the mechanisms through which tumor cells block the immune system are shut off, triggering anti-tumor immune reactions. Clinical trials using immunotherapy drugs that block the binding of the PD-1 receptor to PD-L1 have yielded remarkable results. Despite the excitement surrounding these therapies, the mechanisms by which PD-L1 is activated in cancer cells remains poorly understood. Thus, there is a critical need to understand how this pathway is regulated since a better understanding of how PD-L1 is controlled may provide new therapies to trigger immune responses. Drugs that inhibit PD-L1 have variable responses in lung cancer patients, so this tumor type could greatly benefit from improved immunotherapy strategies targeting this pathway. My lab used cutting-edge technology to test thousands of genes to identify new regulators of PD-L1 in human lung cancer cells. These experiments revealed new genes that positively or negatively regulate PD-L1. We found that initiation of a cellular stress response pathway known as the integrated stress response (ISR) increases PD-L1 translation. This pathway may broadly regulate additional immune checkpoint proteins. In this proposal, we aim to elucidate the mechanisms by which this pathway regulates immune checkpoints and determine whether the ISR can be modulated to improve cancer immunotherapy. We anticipate that these studies will provide new opportunities to harness the immune system to treat lung cancer patients.

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