Impact of intratumor heterogeneity on anti-tumor immune responses in non-small cell lung cancer

• Applicant: Dr. Malte Carl Rörden
• Subject Area: Hematology, Oncology
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462309583

T-cell based immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) and many other malignancies. Response however remains limited to a subset of patients and shows inexplicable variation. Moreover, the factors governing an effective anti-tumor immune response remain incompletely understood. Immune-mediated tumor rejection is based on the recognition of tumor-associated neoantigens by T cells. Of note, recent reports suggest that the neoantigen architecture within a tumor directly impacts the efficacy of anti-tumor immune responses: Homogenous tumors, defined by a high clonal neoantigen burden were found to be associated with an inflamed tumor microenvironment and improved responses to immunotherapy, whereas tumors with high intratumor heterogeneity (ITH) lack immune infiltration and respond poorly to immunotherapy. However, to date there is no mechanistic insight into how ITH affects anti-tumor immunity. Understanding how ITH enables immune evasion is critical not only to improve prediction of response but might enable the development of novel strategies to augment anti-tumor immune responses against heterogenous tumors. The proposed project therefore aims to elucidate the mechanism(s) underlying the negative impact of ITH on anti-tumor immune responses in NSCLC. As tumor heterogeneity, a consequence of the natural co-evolution of tumor and the immune system, is a dynamic process, in vivo studies using autochthonous tumor models portray the optimal setting to study the significance of ITH in cancer immunity. To this end, we aim to establish genetically engineered in vivo NSCLC mouse models (GEMMs) with defined degrees of ITH. A well-established GEMM expressing a mutant, oncogenic KRAS with a conditional knockout of p53 will form the backbone of these models. Intranasal application of recombinant lentiviral vectors subsequently allows to initiate sporadic tumor growth and to introduce either single or multiple neoantigens in these tumors. Different vector combinations then allow to model different degrees of ITH in a highly controlled setting. Using these GEMMs, we will determine the kinetics as well as the functional properties of spontaneous anti-tumor immune responses depending on the extend of ITH. Next, we aim to elucidate the bottlenecks restraining anti-tumor T-cell responses against tumors with high ITH. Last and informed by the insights gained during the study, we will evaluate the capacity of several therapeutic interventions, including neoantigen peptide vaccination, to overcome ITH’s negative impact on anti-tumor immune responses. Upon completion of the project, we will have gained a detailed mechanistic understanding of the dynamics and the immune cells involved in mediating immune evasion in high ITH tumors. This will enable the development of novel strategies to augment anti-tumor immune responses in heterogenous tumors, ultimately allowing more cancer patients to benefit from immunotherapy.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Stefani Spranger, Ph.D.