164P - Disentangling the Joint and Distinct Immunomodulation and Vulnerability Between KEAP1/NFE2L2 and SMARCA4 Alterations in Lung Adenocarcinoma

Background

KEAP1 and SMARCA4 mutations are two extensively studied alterations in lung adenocarcinoma (LUAD). Recent studies have proposed that SMARCA4 mutations can mimic the transcriptional profile of KEAP1/NFE2L2 mutations, suggesting they might share mutual targets. However, SMARCA4 mutations have been shown to confer a poor prognosis and affect immunotherapy efficacy, independent of KEAP1 status. Thus, both mutations conceivably have non-overlapping effects on the tumor microenvironment, but their joint and distinct influences are unclear.

Methods

Using 585 LUAD patients, we conducted differential expressed gene (DEG) and enrichment analyses separately for KEAP1/NFE2L2-MUT and SMARCA4-MUT tumors vs their WT counterparts. Only pathogenic mutations were considered. To avoid confounding effects, tumors with SMARCA4 mutations were excluded when analyzing KEAP1/NFE2L2 mutations, and vice versa. Tumors with EGFR mutations were also excluded, as the two mutations were enriched in EGFR-WT tumors.

Results

The KEAP1/NFE2L2 and SMARCA4 mutations shared upregulated DEGs from the aldo/keto reductase superfamily (AKR1C1, AKR1C2, AKR1C3, AKR1C4). These genes are activated by the KEAP1/NFE2L2 pathway and execute cytoprotective and stress responses. Meanwhile, a larger proportion of their DEGs were mutation-specific (Up/Down: KEAP1/NFE2L2, 77.2%/82.6%; SMARCA4, 87.6%/88.7%). The complement/coagulation cascades and proliferation signatures were activated in SMARCA4-MUT tumors but not in KEAP1/NFE2L2-MUT tumors. The depletion of antigen processing and presentation, leukocyte migration, and B cell-related functions were observed in KEAP1/NFE2L2-MUT tumors. Conversely, SMARCA4 mutations did not recapitulate these critical immune depletions.

Conclusions

The KEAP1/NFE2L2-based cytoprotective activity is a joint feature of the two mutations, suggesting that they might both benefit from cytoprotective inhibitors, such as a glutaminase inhibitor. KEAP1/NFE2L2-MUT tumors showed various immunological abnormalities, highlighting the need for identifying targets to reinvigorate the immune response. SMARCA4-MUT tumors may be vulnerable to complement-targeted therapy.

Legal entity responsible for the study

A. Li.

Funding

This study was supported by the National Natural Science Foundation of China (81972898 and 82172713), the Natural Science Foundation of Guangdong Province (2023B1515020008), and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22ykqb15).

Disclosure

All authors have declared no conflicts of interest.