Abstract KRAS mutant lung adenocarcinoma (KM-LUAD) is the most common molecular subtype of lung adenocarcinoma and has a poor prognosis due to resistance to most conventional therapies. Only a small subpopulation of patients benefits from immune checkpoint inhibitors (ICIs) or recently developed KRAS inhibitors and resistance eventually develops. Thus, an urgent unmet need exists for alternative strategies that can complement ICI or targeted therapy to improve responses. KM-LUAD is closely associated with tumor-promoting inflammation, particularly the activation of the IL-6/STAT3 pathway which we have shown promotes tumor progression. In this study, we investigated the potential of targeting STAT3 signaling to enhance treatment responses to ICI therapy. We targeted STAT3 with an oral small-molecule direct STAT3 inhibitor, TTI-101. Starting at 14 weeks of age, when tumors are established, five cohorts of CCSPCre/LSL-KrasG12D (CC-LR) mice that develop lung adenocarcinomas (KM-LUAD mouse model) received IgG, anti-PD-1 mAb 10mg/kg, TTI-101 100mg/kg, TTI-101 plus anti-PD-1 mAb, or no treatment for four weeks. Daily monitoring indicated no significant toxicity from either TTI-101 or anti-PD-1 mAb treatment. Tumor burden was evaluated by lung surface tumor number (LSTN) count and lesion area percentage of lung sections. TTI-101 alone was sufficient to reduce tumor burden. While anti-PD-1 alone did not reduce tumor burden compared to the controls, there was a notable heterogeneity of LSTN, indicating the presence of anti-PD-1 responders and non-responders. Interestingly, the combination of anti-PD-1 with TTI-101 significantly decreased LSTN compared with either controls or anti-PD-1. Histological analysis revealed reduced inflammation in the combination treatment group compared to either controls or anti-PD-1 treatment. Flow cytometric immunoprofiling of lung tissue showed decreased MHC II+ type 1 macrophage (M1) polarization, decreased recruitment and activation of cDC2s, and increased Th17 cells in anti-PD-1 non-responders compared to anti-PD-1 responders, suggesting that poor treatment responses may be due to an immunosuppressive, cancer-promoting tumor microenvironment (TME). Importantly, the addition of TTI-101 to anti-PD-1 significantly increased MHC II+ macrophages along with activated cDC2s and CD8+ T cells (specifically IFNγ+ CD8 T cells), while decreasing Th17 cells. Thus, TTI-101 alone and in combination with ICI reduced KM-LUAD tumor growth; TME studies suggested that TTI-101 reprograms the TME toward an anti-tumor phenotype and supports to use of combination ICI plus TTI-101 for treatment of KM-LUAD to attenuate pro-tumor inflammation, enhance anti-tumor cytotoxic responses, and improve outcomes. This abstract is funded by: NIH/NCI
Deng et al. (Fri,) studied this question.