Identifying lncRNA modulators of T-cell - Tumor cells interaction to enhance immune checkpoint inhibition therapies

Since their first entry into the clinic (Ipilimumab, 2011), checkpoint inhibition therapies (ICTs) unquestionably became a paramount achievement in the treatment of cancer. Immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 and CTLA-4 have yielded enduring antitumor response in a substantial percentage of patients.

Sadly, poor efficacy of ICTs is still evident in some cancer subtypes. Such is the case for non-small lung cancer (NSCLC) and small lung cancer (SCLC) with only 20% of patients presenting a durable antitumor response when treated with ICIs. This divergence in response highlight the need for a better understanding of the molecular mechanisms and pathways orchestrating immune cell and tumor interactions. Increasing treatment response rates has become a very active field of investigation. Long non-coding RNAs (lncRNAs) are a subclass of RNAs, deficient of functional open reading frames (ORFs) and protein-coding capability. Emerging evidence has shown a prominent involvement of lncRNAs in cancer development and progression. Moreover, some lncRNAs have been shown to regulate T-cell activation or evasion. This said, no effort has been led to systematically investigate the role of lncRNAs in immune-cancer relations. This project partially addresses this issue by aiming to identify immuno-modulating lncRNAs. The discovery and further characterization of candidates will be performed thanks to the development of a high-throughput CRISPR interference (CRISPRi) screening platform in the context of co-cultured systems. The model includes a versatile antigen-specific Jurkat derived cell line (2D3) modified with a GFP reporter gene allowing the detection of immune cell activation upon antigen presentation. On the whole, this is an innovative and ambitious project that aims to better understand the place occupied by lncRNAs and cancer immune resistance, potentially providing novel therapeutic targets.