1. Fig. 5 Neoantigen analysis on patient CTE-0013 who achieved clinical benefit.
Neoantigen analysis on patient CTE-0013 who achieved clinical benefit. (A) Expansion of preexisting CD8+ T cell response to neoepitope (from ODZ3; patient CTE-0019) on treatment (left) and increase in the functional avidity of neoepitope ODZ3-specific T cell clones pretreatment and on-treatment (right). (B) Expansion of preexisting CD8+ T cell response to neoepitope (from HHAT; patient CTE-0013) on treatment (left) and increase in the functional avidity of neoepitope HHAT-specific T cell clones pretreatment and on-reatment (right). Data from (A) and (B) show analyses performed with cryopreserved cells after one round of in vitro stimulation. (C) Cumulative data showing the marked increase in the functional avidity of neoepitope-specific (HHAT) T cell clones pretreatment (pre) and on-treatment (on). (D) T cell receptor–β (TCRβ) V-J segments recombination landscape of sorted HHAT neoepitope-specific CD8+ T cells from patient CTE-0013 [neoepitope-specific T cell responses pre- and on-treatment were fluorescence-activated cell sorting–sorted using peptide–major histocompatibility complex (pMHC) multimer complexes]. V and J segments are represented according to their chromosomal location on the x and y axes; the frequency of each recombination is shown on the z axis and highlighted by colors. Analysis of TCR repertoires pre- and on-treatment showed a remarkable diversity of the two populations, with few distinct dominant clones, supporting the hypothesis of new priming of neoepitope-specific T cells by the treatment. TCRα V-J segments recombination are shown in fig. S8. (E) Calculated binding mode of peptide KQWLVWLFL on HLA-A*0206. The peptide is shown in ball and stick, colored according to the atom types; with carbon in dark and light gray for residues buried or exposed to the TCR, respectively. The TCR (D ) was removed for clarity. Trp3 and Trp6 are predicted to be buried in the same pocket [see (F)]. Anchor residues Gln2 and Leu9 are deeply buried in the MHC surface. (F) Calculated binding mode of peptide KQWLVWLFL on HLA-A*0206, centered on the peptide Trp3 and Trp6 residues. MHC residues are shown in thick lines, colored according to the atom types, with carbon colored in brown. The side chains of peptide residues Leu4 and Val5 were removed for clarity. (G) Calculated TCR/pMHCs for D1 (pre-Vx)–TCRα (111105)–TCRβ (139954), on the left, and D83 (on-Vx)–TCRα (79822)–TCRβ (139954) on the right. TCRα is colored in light blue. Hydrogen bonds and ionic interactions are shown as thin blue lines. Residues are labeled in brown, black, and blue for MHC, peptide, and TCRα, respectively. More numerous favorable interactions can be found between pMHC and TCRα (79822) (right) than with TCRα (111105) (left) (see table S5). EC50, median effective concentration.
Janos L. Tanyi et al., Sci Transl Med 2018;10:eaao5931
Published by AAAS