Immune-resistant mechanisms in cancer immunotherapy

  • Yutaka KawakamiEmail author
  • Shigeki Ohta
  • Mohammad A. Sayem
  • Nobuo Tsukamoto
  • Tomonori Yaguchi
Invited Review Article


Immune checkpoint inhibitors (ICI) such as PD-1/PD-L1 antibodies (Abs) and CTLA4 Abs and T cell-based adoptive cell therapies are effective for patients with various cancers. However, response rates of ICI monotherapies are still limited due to lack of immunogenic antigens and various immune-resistant mechanisms. The latter includes adaptive immune resistance that is caused by anti-tumor T cells (e.g. PD-L1 induced by IFN-γ from T cells) and primary immune resistance that is caused by cancer cells (e.g. immunosuppressive cytokines produced by cancer cells). Further understanding of the immune-resistant mechanisms, which may be possible through comparative analyses of responders and non-responders to the immunotherapies, will lead to the identification of new diagnostic biomarkers and therapeutic targets for development of effective cancer immuno therapies.


Immune checkpoint inhibitor Neo-antigen Oncogene TGF-β Immunometabolism Microbiota 



This work was supported by Grants-in-aid for Scientific Research (26221005) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and the Project for Cancer Research And Therapeutic Evolution (P-CREATE) (16cm0106305h0001) from Japan Agency for Medical Research and Development (AMED).

Compliance with ethical standards

Conflict of interest

Y. Kawakami is an advisor for Taiho Pharma Co. Ltd., has received honoraria from Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, MSD, Chugai, AstraZeneca, and has received research funding from Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, Kowa, JSR, Dainippon Sumitomo Pharma Co. Ltd., and Carna BioSciences, Inc. Other co-authors have no conflict of interest.

Ethical standards

The authors comply with the ethical standards of the journal.

Ethical approval

All of the authors’ studies with human participants are approved by the Keio University ethics committee and appropriately performed.


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Copyright information

© Japan Society of Clinical Oncology 2020

Authors and Affiliations

  • Yutaka Kawakami
    • 1
    • 2
    Email author
  • Shigeki Ohta
    • 2
  • Mohammad A. Sayem
    • 2
  • Nobuo Tsukamoto
    • 2
  • Tomonori Yaguchi
    • 2
  1. 1.International University of Health and Welfare School of MedicineChibaJapan
  2. 2.Division of Cellular Signaling, Institute for Advanced Medical ResearchKeio University School of MedicineTokyoJapan

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