Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens

Abstract

The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens.Experimental Design: PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol.Results: T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4 þ and CD8 þ T cells were specific for p53 R175H , p53 Y220C , or p53 R248W neoantigens, including a 78% reactive T-cell culture against p53 R175H and HLA-A Ã 02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen-reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation-specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens.Conclusions: PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses.See related commentary by Olivera et al., p. 1203

Advances in immunotherapy for hepatocellular carcinoma

“…Some neoantigens arising from driver mutations are shared by different tumours and patients (for example, mutations in TP53 (ref. 28 )), but most are private neoepitopes resulting from seemingly passenger somatic mutations 29 .…”

Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

“…TCRs from CD4+ and CD8+ T cells reactive to mutant p53 neoantigens were identified in lung cancer patients and then TCR-T cells were engineered that recognize the same HLA/neoantigen complex. In follow-up experiments they isolated PBLs from patients with mutant p53 (R175H, Y220C, R248W) tumors by sorting antigen-experienced CD4+ and CD8+ T cells ( 75 ). The T cells were then stimulated with p53 neoantigens (naturally occurring processed and presented peptides) in vitro to confirm the recognition and specificity of the immune response.…”

TP53abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

“…Interestingly, 40% of patients with solid tumors display T-cell responses to TP53 hotspot mutations which are mediated by both CD4 + and CD8 + T cells (55), underpinning the broad immunogenicity of TP53 neoepitopes. In this respect, antigen-experienced T cells have been expanded ex vivo from nine patients with metastatic epithelial cancers expressing a hotspot TP53 mutation and have been successfully screened for neoantigen responses (56). This observation raises the hypothesis that the presence of immunogenic TP53 mutations accounted for the higher degree of immune infiltration and activation in our patient cohorts with TP53 mutated AML, as also suggested by studies in solid tumors (20,57).…”