Cell
Volume 184, Issue 19, 16 September 2021, Pages 4981-4995.e14
Journal home page for Cell

Article
The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function

https://doi.org/10.1016/j.cell.2021.08.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • CAR-T cells deliver RN7SL1 in extracellular vesicles (EVs) and activate RIG-I

  • CAR-T cells expressing RN7SL1 show greater expansion and persistence and less exhaustion

  • Preferential uptake of RN7SL1 by DC/myeloid over tumor cells enhances endogenous immunity

  • CAR-T EVs can co-deliver antigen with RN7SL1 to reject tumors with CAR antigen loss

Summary

Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens.

Keywords

CAR-T cells, RN7SL1, 7SL, pattern recognition receptors, RIG-I, MDA5, interferon, exosomes, extracellular vesicles

Data and code availability

  • Single-cell RNA-seq data have been deposited at the GEO and are publicly available as of the date of publication. Accession numbers are listed in the Key resources table.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

7

Lead contact