Tricking tumor immunosuppression: RNA epigenetics as novel target to improve cancer immunotherapy (EPIMAC)

Immunotherapy is considered as a major breakthrough in the treatment of cancer, but still a large fraction of
the patients are not responsive and several cancer types are refractory to this therapy. The presence of a
strongly immune suppressive environment within primary tumors and at the metastatic site is a likely explanation for the suboptimal efficacy of immunotherapy, with tumor-associated macrophages (TAMs) and
metastasis-associated macrophages (MAMs) as important immune suppressive cells.
In this project, we will assess whether RNA modifications (so-called RNA epigenetics) are sculpting the tumorpromoting
behaviour of TAMs and MAMs. Hereto, we will employ state-of-the-art technology to establish the
transcriptomic diversity and intratumoral localization of TAM and MAM populations in non-small cell lung
carcinoma and triple-negative breast carcinoma tumor models. In vivo genetic screens in macrophages will
identify target genes, involved in the epigenetic control of RNA species, that have the capacity to re-educate
macrophages resulting in enhanced anti-tumor immunity and reduced tumor growth and metastasis.
Ultimately, we will assess a pharmacological inhibition of these novel target molecules to encourage the
development of novel immunotherapeutics which are urgently required to tackle tumor resilience or resistance
vis-à-vis immunotherapies.