Background A population of MR1-restricted T cells (MR1T) which responds to tumor-associated antigens has been studied. The MR1T can kill tumor cells from various tissue origins across the MHC barriers, but inert to non-cancerous cells.1 These T cells appears to have a potential to be a safe anti-cancer therapeutics overcoming the HLA-restriction of conventional αβ T cells.2 We have developed Panck T cells, pan-cancer-killing CD8+ T cells, to examine their potential as a therapeutic in human trials.
Methods We induced anti-cancer MR1T by stimulating peripheral T cells with cancer cells that were prepared to over express MR1 but not express HLA. MR1T cells with anti-cancer activities were purified and subjected to a rapid expansion in a large scale. These cells were phenotyped, assayed for cancer killing activities in both in vitro, and in vivo. Finally, the TCR sequences of the Panck T cells were analyzed to characterize TCR clones associated with the anti-cancer activities of Panck T cells.
Results We established a method of isolating and expanding MR1-restricted Panck T cells at high purity, and confirmed that these cells showed cytotoxicity, IFN-γ and TNF responses to various target cancer cells. They showed strong anti-cancer activities in animal models of various hematologic and solid cancers. We isolated high purity of CD8+ 4-1BB+ T cells except CD8+ TCRva7.2+ T cells, which are MAIT cells after primary induction of Panck T. Final products have characteristics of phenotype, usually CD69hi, CD161- TCRvα7.2-, CD62Lmed, CD45RO+, CD57-, and PD-1-, and have shown anti-cancer activities against multiple cancers in both in vitro, and in vivo animal models. Expression of a representative TCR on T cells mediated anti-cancer effects against multiple cancers comparable to the Panck T itself.
Conclusions In conclusion, we have developed and standardized the isolation and expansion method of Panck T, which showed a strong anti-cancer activity to various types of cancers regardless of their HLA types.
Crowther MD, Dolton G, Legut M, Caillaud ME, Lloyd A, Attaf M, Galloway SAE, Rius C, Farrell CP, Szomolay B, Ager A, Parker AL, Fuller A, Donia M, McCluskey J, Rossjohn J, Svane IM, Phillips JD, Sewell AK. Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat Immunol. 2020;21(2):178–185.
Lepore M, Kalinichenko A, Calogero S, Kumar P, Paleja B, Schmaler M, Narang V, Zolezzi F, Poidinger M, Mori L, De Libero G. Functionally diverse human T cells recognize non-microbial antigens presented by MR1. Elife. 2017;6:e24476.
Ethics Approval Approval has been granted by the Institutional Review Board (IRB) for human-derived material research (NCC2020-0295)
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