Targeting LCN2, a novel therapy for lung cancer

PROJECT SUMMARY/ABSTRACT KRAS-driven non-small cell lung cancer (NSCLC) remains one of the most aggressive and lethal solid tumors. Current NSCLC therapies, although promising, have low efficacy against KRAS-driven LUAD. Because KRAS mutant tumors are resistant to standard-of-care treatments, there is an urgent clinical need to identify both druggable tumor-intrinsic vulnerabilities and approaches to boost responses to standard-of-care therapies. The Integrated Stress Response (ISR) enables tumors to overcome growth limitations and therapeutical interventions. However, little is known about how ISR activation in tumor cells impacts the microenvironment (TME). In our preliminary studies, we found that loss of ATF4, a major arm of ISR, inhibits tumor growth in immunocompetent animals in a T cell-dependent manner, strongly suggesting that tumoral ISR promotes immune evasion via induction of immunosuppressive molecules. Indeed, using a CRISPR/Cas9 genetic screen targeting ISR-responsive genes, we identified Lipocalin 2 (LCN2), a small glycoprotein, as a potent immunomodulatory molecule that suppresses anti-tumor T cell responses. LCN2 is upregulated in many challenging tumor types and is associated with poor prognosis. LCN2 is distinct from checkpoint molecules that have been studied in that it is a secreted molecule rather than a surface receptor. Thus, we hypothesize that LCN2 offers a novel therapeutic opportunity that complements the current immune checkpoint blockade (ICB). Our preliminary studies revealed that LCN2 is associated with T-cell exclusion in patient samples as well as in mouse models. We have developed human synthetic antibodies against mouse and human LCN2, and these antibodies are efficacious in the inhibition of tumor growth and in increasing T-cell infiltration in mouse models. Based on these exciting data, we propose the following Aims to define the role of LCN2 in the TME and develop a therapeutic strategy in lung cancer: 1) Characterize the impact of LCN2 on the composition of the TME; 2) Develop novel biological therapeutics that interfere with LCN2 and assess their efficacy as monotherapy as well as in combination with ICB; and 3) Determine the mechanism of action of LCN2 by utilizing a combination of genetically engineered models and a panel of anti-LCN2 antibodies. These studies will establish the mechanism of action of LCN2 in the TME, its use as a potential marker of immune evasion, and novel therapies that neutralize LCN2 function that may help overcome ICB non-responsiveness in lung cancer and potentially other challenging cancer types.