207P Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small cell lung cancer

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and immunotherapy resistance. Lurbinectedin is FDA-approved as a second-line treatment for SCLC, and we previously showed it as an effective therapeutic strategy in SCLC. However, there is no insight into the effect of lurbinectedin on the immune microenvironment in SCLC. In this study, we evaluated the effect of lurbinectedin on the immune microenvironment and the anti-tumor effect with or without PD-L1 blockade. We treated immunocompetent flank RPP (Rb1, Trp53, and p130) and RPM (Rb1, Trp53, and MYCT58A) with lurbinectedin and/or anti-PD-L1 and analyzed the tumors by multi-color flow cytometry, single cell and bulk RNA sequencing, western blot and RT-PCR. Anti-PD-L1 alone showed no anti-tumor response, and single-agent lurbinectedin caused a delay in tumor growth in this model. However, of the 10 mice treated with the combination of lurbinectedin and anti-PD-L1, 2 had a complete tumor regression and the other 4 had 90% tumor regression. Tumors were resected on Day 21 and analyzed by multicolor flow cytometry for changes in tumor-infiltrating lymphocytes (TILs). We demonstrate significant induction of cytotoxic T cells and a reduction of exhausted and regulatory T cells in the lurbinectedin+PD-L1 treatment arm. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased, while immunosuppressive M2 type macrophages and MDSC cells were decreased. These effects are consistent with data showing that lurbinectedin treatment leads to an activation of the cGAS/STING pathway, type I/II interferons (IFNα/β), and pro-inflammatory chemokines (CCL5, CXCL10) in tumors. Interestingly, lurbinectedin treatment led to significant upregulation of mRNA and surface expression of MHC class-I genes (HLA-A/B/C) in vitro and in vivo. We provide the first mechanistic insight into the lurbinectedin induced multimodal immune modulation in SCLC leading to a dramatic anti-tumor activity accompanied by the establishment of a strong anti-tumor immune microenvironment. Our preclinical data provide a strong rationale for combining this regimen with inhibitors of the PD-L1 pathway.