Editors' ChoiceCancer Immunotherapy

Less is more for adoptive immunotherapy?

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Science Translational Medicine  01 Jul 2020:
Vol. 12, Issue 550, eabd3077
DOI: 10.1126/scitranslmed.abd3077


p38 inhibition augments adoptive T cell therapy by making T cells “fitter.”

T cells are the circulating soldiers of our adaptive immune system, exemplified by their capacity to distinguish the minute differences between the self and non-self antigens typically found on tumors. T cells are the primary targets in recent therapeutic modalities of immunotherapy such as immune checkpoint blockade and adoptive T cell therapy. Whereas checkpoint blockade, by releasing “immunosuppressive brakes,” rejuvenates “exhausted” endogenous T cells to induce effective antitumor responses, adoptive T cell therapy relies on infusion of well-equipped T cells (super-soldiers) to cure tumors. As such, how to produce therapeutically fit T cells to conquer the harsh tumor microenvironment is key to its clinical success.

By performing a systemic literature review and elegantly designed experiments, Gurusamy et al. selected cell expansion, memory-like properties, and low amounts of reactive oxygen species (ROS) and γH2AX (a readout of DNA damage) as essential features of therapeutically effective antitumor T cells. To enrich these phenotypes in T cells, they used CRISPR-Cas9 to delete kinases with sustained activity downstream of T cell receptor (TCR) signaling. Intriguingly, among the 25 targeted kinases, deletion of p38α kinase arose as the only effective modulation to improve all four characteristics. They applied pharmacological inhibition of p38α (p38αi) and observed that p38αi phenocopied genetic deletion of p38α with regard to improving the aforementioned phenotypes of T cells, particularly in CD8+ T cells. Last, they incorporated p38αi in their clinical scale rapid expansion protocol for human T cells as well as in the generation of tumor antigen-specific T cells, including αCD19 CAR-T cells. Their results indicated that p38αi led to augmented cell survival and memory T cell–associated markers as well as enhanced effector function. Most importantly, ex vivo p38αi-preconditioned T cells, upon transfer into tumor-bearing mice, markedly suppressed tumor growth and improved mouse survival, paving the way for clinically relevant interventions.

Despite these exciting results, additional information is needed. Given that p38α is a key kinase transducing signals from TCR stimulation that are essential for T cell activation and function, it would be interesting to determine how p38αi drives T cell expansion and effector functions. To this end, the involvement of the other two key signaling pathways such as PI3K-AKT-mTOR and NF-κB, downstream of TCR signaling, should be examined. Further understanding of why p38αi preferentially affects CD8+ T cells may reveal important therapeutic insights for adoptive immunotherapy.

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