Immunotherapy has revolutionised the treatment of lung cancer patients, however, response rates are low. Lung cancers that harbour concurrent mutations in KRAS, STK11(LKB1) and KEAP1 (KLK tumours) fail to derive benefit from PD(L)-1 inhibition alone. A greater understanding of the cell-intrinsic processes that allow these tumours to evade immune detection is required to enhance therapeutic outcomes.
To directly address this, we employed an unbiased CRISPR/Cas9 knockout co-culture screen to identify gene targets that sensitise lung cancer cells to T cell-mediated killing. Briefly, Keap1 was inactivated in cell lines generated from lung tumours that arose in KrasLSL-G12D/+;Lkb1f/f (KL) mice. KLsgKeap1 (KLK) cells were then engineered to express the OVA peptide antigen and infected with a whole-genome CRISPR-Cas9 library, followed by serial application of OT-I T cells. Excitingly, sgRNAs targeting a deubiquitylating (DUB) enzyme were found to sensitise KLK tumour cells to T cell killing. In vitro and in vivo studies validating that inactivation of the candidate DUB in KLK cells enhances anti-tumour immunity will be presented. Mechanistically, a correlation between high candidate DUB expression and lung cancers harbouring KEAP1-NRF2 pathway alterations was observed, suggesting that selective targeting of the candidate DUB may serve as an ‘Achilles heel’ in tumours with KEAP-NRF2 pathway activation. Importantly, analysis of publicly available lung cancer patient datasets revealed significant associations between low expression of the candidate DUB, enhanced immune infiltration and improved response to immunotherapy.
Taken together our studies demonstrate that the candidate DUB serves as a novel immunotherapeutic target for the treatment of lung cancer.