Dissecting and targeting SUMOylation to increase the efficacy of lymphoma immunotherapy

• Applicant: Professor Dr. Ulrich Keller
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508460329

The reversible post-translational modification of cellular proteins by the ubiquitin-related SUMO modifiers (SUMOylation) has emerged as a crucial regulatory mechanism in many key cellular pathways. SUMO signaling is instrumental for maintenance of genome integrity, control of gene expression, cell proliferation, and for immune responses to various challenges. The cellular SUMOylation state is tightly controlled by the balanced activity of the multi-step enzymatic SUMO conjugation machinery and the SUMO deconjugation pathway. Alterations of SUMO homeostasis are frequently observed in cancer and associated with an aggressive phenotype and poor prognosis. We previously identified enhanced SUMOylation as a therapeutic vulnerability for B cell lymphoma (BCL) and solid cancers characterized by dependency on the oncoprotein MYC. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we have identified an evolutionary conserved function of activated SUMOylation, which attenuates the immunogenicity of tumor cells. Activated SUMOylation allows cancer cells to evade CD8+ T-cell-mediated immunosurveillance by suppressing the MHC-I antigen processing and presentation machinery (APM). While deficiency of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, the pharmacological inhibition of SUMOylation (SUMOi) led to loss of the transcriptional repressor SAFB and to induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T-cell mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T-cells itself and thereby drives a feed-forward loop amplifying the specific anti-tumor immune response. We thus found that activated SUMOylation converts tumor cells into a state of immune evasion, and identify SUMOi as rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies. To translate the concept of SUMOi into clinical application, a precise understanding of the mechanisms of SUMO-mediated immune escape as well as effects on immune cell abundance and immune cell function is required. We here aim to i) identify tumor-intrinsic mechanisms of activated SUMOylation relevant for immune escape; ii) decipher the role of SUMOylation for formation of a permissive tumor microenvironment (TME); iii) evaluate in vivo consequences of SUMOi within the TME; and iv) deliver therapeutic strategies targeting SUMO-mediated immune escape and the permissive TME for translation into clinical trials.

• DFG Programme: Research Grants