Understanding and therapeutically harnessing the tumor-supportive and immune-suppressive functions of TRAIL and CD95L in SCLC (C06)

G. Liccardi和H. Walczak将利用他们在第一个资助期内的发现，显示用TRAIL或CD 95 L（FasL）阻断剂治疗的RP小鼠（SCLC GEMM）的生存期延长。这种方法提供的显著治疗优势现在将扩展到SCLC的更具免疫原性的GEMM，即RPM模型，其中存在增加的肿瘤突变负荷，并且已经由A01在这种CRC的背景下开发。他们将研究在这种模型的背景下，观察到的抑制TRAIL或CD 95 L的治疗效果在多大程度上分别取决于肿瘤细胞的内在效应和外在效应。此外，他们将研究抑制TRAIL和/或CD 95 L是否与新抗原性增加的SCLC小鼠模型中的ICI协同作用。此外，与C 05/C 08合作，他们将确定死亡配体阻断（有或没有ICI）是否也可以在RPM模型中与基于mRNA的新抗原靶向疫苗协同作用。

G. Liccardi and H. Walczak will capitalize on their findings made in the first funding period showing survival extension of RP mice (SCLC GEMM) treated with TRAIL or CD95L (FasL) blockers. The significant therapeutic advantage offered by this approach will now be extended to a more immunogenic GEMM of SCLC, the RPM model, in which there is an increased tumor mutational burden and which has been developed by A01 in the context of this CRC. They will study to which extent the therapeutic effects observed with inhibition of TRAIL or CD95L depend on tumor cell-intrinsic versus -extrinsic effects, respectively, within the context of such models. Additionally, they will study whether inhibiting TRAIL and/or CD95L synergizes with ICI in SCLC mouse models with increased neoantigenicity. Moreover, in collaboration with C05/C08 they will determine whether death ligand blockade, with or without ICI, may also synergize with mRNA-based neoantigen-targeting vaccines in the RPM model.