Selective inhibition of canonical STAT3 signaling suppresses K-ras mutant lung tumorigenesis and reinvigorates anti-tumor immunity

Michael Joseph Clowers^1,2Zahraa Rahal¹Sung-Nam Cho¹Avantika Krishna^1,2Bo Yuan¹Leticia G Hamana Zorrilla¹T Kris Eckols¹Moses M Kasembeli¹Samuel Liu¹Stephen Peng¹Marco Ramos¹Annamarie L Thompson^1,3Carlos Ignacio Rodriguez Reyna¹Katherine E Larsen¹Maria T Grimaldo^1,2Shanshan Deng¹Nastaran Karimi¹Cody Chou¹Walter V Velasco¹Melody Zarghooni¹Sayan Alekseev¹Luisa Maren Solis Soto¹Edwin J Ostrin¹Humam Kadara¹Suhendan Ekmekcioglu¹David J Tweardy¹Seyed Javad Moghaddam^1*

• ¹University of Texas MD Anderson Cancer Center, Houston, United States
• ²Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas, United States
• ³Mississippi State University, Starkville, Mississippi, United States

K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. One of the lynchpins of chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3). Here, we tested the anti-tumor and early immunotherapeutic efficacy of TTI-101, a selective small-molecule inhibitor of canonical STAT3 signaling, in a K-ras G12D mutant lung cancer mouse model (CC-LR). Treatment of CC-LR mice with TTI-101 resulted in reduced tumor burden while increasing dendritic cell (DC) and T helper 1 (Th1) infiltration into the TIME. TTI-101 treatment decreased pY-STAT3 expression in tumors with accompanying increases in several NF-κB anti-tumor target genes including CXCL9, a chemokine for primed T cells. Transcriptional profiling of the TIME revealed improved immune activation and anti-tumor skewing, as well as B cell signaling enrichment. Analysis of human LUAD data demonstrated negative correlations between STAT3 and Th1/DC infiltration, with DC infiltration also conferring improved survival in LUAD patients with low STAT3. Our results highlight the importance of STAT3 in driving early tumorigenesis and offer a preventative treatment window for high-risk individuals and patients with early-stage KM-LUAD.