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Abstract 1320: Immunogenomic analysis identifies the complement pathway as a therapeutic target in STK11 mutant non-small cell lung cancer


 Background: The use of immune PD-1/-L1 checkpoint inhibitors (ICI) has dramatically altered the treatment of advanced non-small cell lung cancer (NSCLC). However, a large proportion of patients with NSCLC do not derive clinical benefit from ICI treatment. Recent studies have identified certain genomic subsets of NSCLC as drivers of primary resistance to ICI treatment.
 Methods: We evaluated NSCLC patients treated at Roswell Park Comprehensive Cancer Center from 2017-2020 with successful genomic and immune profiling using a CLIA-certified laboratory developed test that included targeted next-generation genomic sequencing, PD-L1 assessment by immunohistochemistry (IHC), and targeted RNA-seq of 394 immune transcripts.
 Results: A total of 379 treatment-naive non-squamous NSCLC subjects were identified with 113 subjects treated with an FDA approved ICI regimen and evaluable for response. Using a gene expression signature based on differential gene expression analysis in the 113 subjects with and without disease control with ICI treatment, we performed unsupervised clustering of the larger 379 subject cohort and identified a responder (R) cluster and non-responder (NR) cluster. The R cluster was associated with high PD-L1 expression, T-cell infiltration, and KRAS mutations. The NR cluster was associated with negative PD-L1 expression, lack of T-cell infiltration, and mutations in STK11, APC/CTNNB1, and NFE2L2. Of the mutation subsets, STK11 was most associated with NR with a trend towards lower PD-L1 expression by clinical IHC, but much more significantly associated by gene expression signatures with low PD-L1 and T-cell inflammation. In our gene panel, we identified elevated TRIM29 expression in STK11 mutant NSCLC tumors and confirmed TRIM29 expression by IHC on a separate 64 subject cohort with known STK11 mutation status and archival formalin fixed paraffin embedded (FFPE) tissue. A subset of STK11 mutant NSCLC cell lines also demonstrated elevated TRIM29 expression and we generated knockouts of TRIM29 with CRISPR-Cas9 in these cell lines which resulted in decreased tumor growth in xenograft models. Using Nanostring nCounter multiplex inflammation gene expression panel on both the 64 patient FFPE cohort and TRIM29 knockout cell lines, we identified the innate immune complement pathway as a target of therapeutic interest and specifically the high expression of complement component C3 by TRIM29 high tumor cells. We then generated a syngeneic mouse model where loss of Stk11 resulted in elevated expression of Trim29 and C3 for preclinical studies to evaluate the therapeutic modulation of the complement pathway on response to ICI.
 Conclusion: Using a large clinical cohort of non-squamous NSCLC patients we characterized the immune environment of mutational subsets of NSCLC and identified the complement pathway as a potential therapeutic target in STK11 mutant NSCLC.
 Citation Format: Edwin H. Yau, Bojidar Kandar, Lei Deng, Te-An Chen, Wiam Bshara, Sean Glenn, Sarabjot Pabla, Antonios Papanicolau-Sengos, Mary Nesline, Hongbin Chen, Amy Early, Carl Morrison, Grace Dy. Immunogenomic analysis identifies the complement pathway as a therapeutic target in STK11 mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1320.