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Monitoring PD-1-Blocking Antibodies Bound to T Cells Derived from a Drop of Peripheral Blood
Published on: February 5, 2020
Immunotherapies targeting neoantigens are effective in PD-1 blockade-resistant tumors
Changbo Sun1,2,3, Koji Nagaoka1, Yukari Kobayashi1
1Department of Immunotherapeutics, University of Tokyo Hospital, Tokyo, Japan.
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.
Insights
Researchers identified new cancer neoantigens to improve T cell therapies for tumors resistant to PD-1/PD-L1 blockade. This approach enhances the immune system
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Limited efficacy of current immunotherapies like PD-1/PD-L1 blockade for certain tumors.
- Need for strategies to enhance anti-tumor T cell responses in resistant cancers.
Purpose of the Study:
- To identify novel immunogenic neoantigens for enhancing T cell-mediated cancer immunotherapy.
- To develop strategies to overcome resistance to PD-1/PD-L1 blockade therapy.
Main Methods:
- Whole-exome and RNA sequencing to identify mutations in murine lung cancer (ASB-XIV).
- In silico prediction of MHC-I binding affinity for neoepitope peptides.
- Screening of neoepitope peptides using ASB-XIV-specific CD8+ T cells.
- Vaccination with dendritic cells (DCs) pulsed with identified neoepitopes (mPhf3, mCdt1).
- Combination therapy with anti-PD-1 treatment and adoptive T cell transfer.
Main Results:
- Identification of mutated Phf3 peptide (mPhf3) as an immunogenic neoepitope.
- mPhf3-DC vaccination inhibited ASB-XIV tumor growth via CD8+ T cell immunity.
- Combination of mPhf3-DC vaccine and anti-PD-1 therapy showed robust anti-tumor activity.
- Adoptive transfer of mPhf3-specific CD8+ T cells eradicated ASB-XIV tumors.
- Similar positive results observed with mCdt1 in PD-1 blockade-resistant gastric tumors (YTN16).
Conclusions:
- A novel immunogenic neoepitope (mPhf3) was identified for ASB-XIV tumors, offering a new target for cancer immunotherapy.
- Identifying immunogenic neoantigens can increase the frequency of neoantigen-specific T cells, improving therapeutic strategies for PD-1/PD-L1 blockade-resistant tumors.
- This approach holds promise for expanding the effectiveness of cancer immunotherapies.
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