TY - JOUR
T1 - Adenoviral-based vaccine promotes neoantigen-specific CD8+ T cell stemness and tumor rejection
AU - D’Alise, Anna Morena
AU - Brasu, Nadia
AU - De Intinis, Carlo
AU - Leoni, Guido
AU - Russo, Valentina
AU - Langone, Francesca
AU - Baev, Denis
AU - Micarelli, Elisa
AU - Petiti, Luca
AU - Picelli, Simone
AU - Fakih, Marwan
AU - Le, Dung T.
AU - Overman, Michael J.
AU - Shields, Anthony F.
AU - Pedersen, Katrina S.
AU - Shah, Manish A.
AU - Mukherjee, Sarbajit
AU - Faivre, Thea
AU - Delaite, Patricia
AU - Scarselli, Elisa
AU - Pace, Luigia
N1 - Publisher Copyright:
© 2022 The Authors, some rights reserved.
PY - 2022/8/10
Y1 - 2022/8/10
N2 - Upon chronic antigen exposure, CD8+ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)–vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti–programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.
AB - Upon chronic antigen exposure, CD8+ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)–vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti–programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.
UR - http://www.scopus.com/inward/record.url?scp=85136339597&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abo7604
DO - 10.1126/scitranslmed.abo7604
M3 - Article
C2 - 35947675
AN - SCOPUS:85136339597
SN - 1946-6234
VL - 14
JO - Science translational medicine
JF - Science translational medicine
IS - 657
M1 - eabo7604
ER -