The novel lncRNA SEAL1 - key regulator of the pan-cancer myCAF cell state dictating prognosis ans immunotherapy response - is a promising new therapeutic target for solid cancers

A desmoplastic reaction in the solid tumor microenvironment (TME), typically characterized by extracellular matrix (ECM) dysregulation and an immune suppressive milieu, is a key factor contributing to tumor aggression, therapeutic resistance, metastasis and inevitably poor patient prognosis. Cancer-associated fibroblasts (CAFs), in particular myofibroblast-like CAFs (myCAFs), are central players in the development of TME desmoplasia in the most common and aggressive solid cancers such as breast, lung, head & neck and pancreatic. The contribution of myCAFs to standard-of-care treatment resistance and immunotherapy failure has raised their attraction as therapeutic targets. However, myCAF-targeting therapies have not yet proven to be effective for clinical use and is still a largely unexplored area of solid cancer therapeutics. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of epigenomic and transcriptomic cellular processes and characterized by highly cell-state and disease-specific expression. Targeting myCAF-specific regulatory lncRNAs constitutes a novel therapeutic approach to reduce myCAF-driven detrimental changes in the TME, coupled to an increased susceptibility to combination treatments. Here we identified a novel lncRNA SEAL1 which is restrictively expressed in the pan-cancer myCAF cell state associated with poor patient prognosis and treatment response. Independent analyses of breast, head & neck and pancreatic cancer patient datasets demonstrated SEAL1 as a key component of disease-driving myCAF co-regulatory networks. By antisense oligonucleotide (ASO)-mediated targeting of SEAL1, and of the murine functional analog Seal1 , we demonstrated that the myCAF identity was potently reduced in in vitro cellular models. In contrast, ASO- or CRISPRi-mediated targeting of LRRC15/Lrrc15 , a SEAL1 downstream marker associated with the myCAF cell identity, had no effect on the disease-driving myCAF cell state. LRRC15 has previously been associated with poor prognosis and an unfavorable response to immunotherapy, being actively pursued as a potential CAF therapeutic target. Moreover, by utilizing a xenograft co-injection in vivo model, SEAL1 targeting in patient-derived myCAFs reduced tumor volume whereas LRRC15 targeting had no effect. Taken together, this study emphasizes that the Regulatory Genome is still largely under explored and that novel discoveries such as SEAL1 may uncover previously unknown biological mechanisms. By leveraging regulatory lncRNAs as potent modifiers of specific disease-states, we conclude that the SEAL1 lncRNA is a major determinant of myCAF pro-tumorigenic transcriptional programs of therapeutic value.