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- Title
Immunotherapies targeting neoantigens are effective in PD‐1 blockade‐resistant tumors.
- Authors
Sun, Changbo; Nagaoka, Koji; Kobayashi, Yukari; Maejima, Kazuhiro; Nakagawa, Hidewaki; Nakajima, Jun; Kakimi, Kazuhiro
- Abstract
Only a small fraction of tumor‐infiltrating lymphocytes can specifically recognize and attack cancer cells in PD‐1/PD‐L1 blockade therapy. Here, we investigate approaches to expand the neoantigen‐specific CD8+ T cells to overcome the difficulties in treating PD‐1/PD‐L1 blockade‐resistant tumors. Mutation‐associated neoepitopes of murine nonsmall cell lung cancer ASB‐XIV were estimated by whole‐exome and RNA sequencing and predicted by MHC‐I binding affinity (FPKM >1) in silico. Using ASB‐XIV‐specific CD8+ T cells, we screened a panel of 257 neoepitope peptides derived from ASB‐XIV missense and indel mutations. Mutated Phf3 peptide (mPhf3) was successfully identified as an immunogenic neoepitope. Prophylactic mPhf3‐DC vaccination inhibited ASB‐XIV tumor growth through CD8+ T cell‐mediated antitumor immunity. Combining the mPhf3‐DC vaccine and anti‐PD‐1 treatment elicited robust antitumor activity through the induction of mPhf3‐specific CD8+ T cells in the tumor microenvironment. Furthermore, the adoptive transfer of mPhf3‐specific CD8+ T cells eradicated ASB‐XIV tumors. Likewise, the combination of mutated Cdt1 peptide (mCdt1)‐DC vaccine and anti‐PD‐1 treatment or adoptive transfer of mCdt1‐specific CD8+ T cells also led to significant regression of PD‐1 blockade‐resistant murine gastric YTN16 tumors. In conclusion, a novel immunogenic neoepitope of ASB‐XIV was identified for immunotherapy targeting neoantigens. Identification of immunogenic neoantigens can extend the therapeutic strategies by increasing the frequency of neoantigen‐specific T cells, even for PD‐1/PD‐L1 blockade‐resistant tumors.
- Subjects
PROGRAMMED cell death 1 receptors; NON-small-cell lung carcinoma; PEPTIDES; T cells; PROGRAMMED death-ligand 1
- Publication
International Journal of Cancer, 2023, Vol 152, Issue 7, p1463
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.34382