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- W4308378587 abstract "<h3>Background</h3> Adoptive cell transfer (ACT) of neoantigen-reactive CD8<sup>+</sup> T cells has had some success in the clinic; however, mouse models recapitulating neoantigen-reactive CD8<sup>+</sup> T cell ACT have been limited, especially in poorly immunogenic models such as the murine melanoma model B16F10. Further, direct comparison of neoantigen-reactive CD8<sup>+</sup> T cell ACT versus ACT utilizing T cells reactive against overexpressed-self or heteroclitic tumor-associated antigen (TAA) peptides has been lacking. To address these gaps, we developed a model system to study neoantigen- and TAA-reactive CD8<sup>+</sup> T cell ACT in parallel. <h3>Methods</h3> Whole exome sequencing and RNA sequencing were employed to predict neoantigens present in B16F10. C57BL/6 mice were then administered charge-modified TLR7/8 conjugate vaccines targeting neoantigenic peptides predicted to elicit T cell responses. Vaccination against neoepitopes and previously characterized TAA epitopes elicited neoantigen- or TAA- reactive CD8<sup>+</sup> T cells and modest tumor growth control; T cell receptors were isolated from neoantigen- and TAA-reactive CD8<sup>+</sup> T cell clones. To develop an ACT model, we conducted CRISPR/Cas9-mediated knockdown of endogenous TCR and subsequent transduction (g-retrovirus encoding neoantigen- or TAA-reactive TCRs) in murine CD8<sup>+</sup> T cells. T cells were expanded <i>in vitro</i> for use in downstream <i>in vitro</i> and <i>in vivo</i> applications. <h3>Results</h3> Peptide stimulation <i>in vitro</i> of neoantigen- and TAA-reactive T cells revealed wide ranges of 1) specificity (vs. cross-reactivity to wild type peptide), and 2) avidity for cognate peptide. Neoantigen- and TAA-reactive T cells were able to recognize B16F10 cells <i>in vitro</i>, with the most robust recognition (readout:% T cells IFNg<sup>+</sup>) when target antigen is highly expressed by tumor cells. Ability of neoantigen- or TAA-reactive T cells to kill B16F10 <i>in vitro</i> was strongly dependent upon both tumor antigen expression and T cells’ TCR avidity. Similarly, reduction of tumor growth <i>in vivo</i> required both high tumor antigen expression and transfer of high avidity neoantigen- or TAA-reactive CD8<sup>+</sup> T cells. <h3>Conclusions</h3> To conclude, we have created a novel model of neoantigen- and TAA-reactive ACT in immunotherapy-refractory B16F10 melanoma. Our data suggest that antigen abundance and TCR avidity are parameters that influence ACT efficacy; future research will be conducted to dissect the individual and summative contributions of these parameters and translate this knowledge towards improving ACT design in the clinic." @default.
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- W4308378587 date "2022-11-01" @default.
- W4308378587 modified "2023-10-13" @default.
- W4308378587 title "364 Antigen abundance and TCR avidity impact T cell-mediated tumor recognition in novel B16F10 ACT model" @default.
- W4308378587 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0364" @default.
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