Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

Abstract

PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a 'bilateral tumor model' where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited T cell proliferation and mitochondrial activation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that 'bilateral tumor model' was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.

Data availability

We have uploaded qPCR primers sequences related to Supplementary Figure S6 to 'Dryad repositories'. doi:10.5061/dryad.vq83bk3np

The following data sets were generated

Article and author information

Author details

  1. Alok Kumar

    Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Kenji Chamoto

    Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Partha S Chowdhury

    Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Tasuku Honjo

    Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, Japan
    For correspondence
    honjo@mfour.med.kyoto-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2300-3928

Funding

Japan Agency for Medical Research and Development (JP19cm0106302)

  • Tasuku Honjo

Japan Agency for Medical Research and Development (JP19gm0710012)

  • Tasuku Honjo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yutaka Kawakami, Keio University School of Medicine, Japan

Ethics

Animal experimentation: His study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee of Kyoto University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Kyoto University (Permit Number: Medkyo19080). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: October 1, 2019
  2. Accepted: February 11, 2020
  3. Accepted Manuscript published: March 3, 2020 (version 1)
  4. Version of Record published: March 30, 2020 (version 2)

Copyright

© 2020, Kumar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alok Kumar
  2. Kenji Chamoto
  3. Partha S Chowdhury
  4. Tasuku Honjo
(2020)
Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
eLife 9:e52330.
https://doi.org/10.7554/eLife.52330

Share this article

https://doi.org/10.7554/eLife.52330

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