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

Alok Kumar1, Kenji Chamoto1, Partha S Chowdhury1

  • 1Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Elife
|March 4, 2020
PubMed

Insights

Unresponsive tumors to PD-1 blockade therapy exhibit distinct mechanisms, including systemic immunosuppression or immune evasion via MHC class I loss. Identifying these differences is key to developing effective combination therapies for cancer patients.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Programmed cell death protein 1 (PD-1) blockade therapy has transformed cancer treatment but faces challenges with patient non-responsiveness.
  • Understanding the mechanisms underlying non-responsiveness is crucial for improving therapeutic outcomes in a significant patient population.
  • Current strategies lack stratification for diverse non-responsiveness mechanisms.

Purpose of the Study:

  • To elucidate the distinct mechanisms of non-responsiveness to PD-1 blockade therapy.
  • To categorize non-responsive tumors based on their properties.
  • To evaluate the utility of a bilateral tumor model for stratifying non-responsiveness mechanisms and guiding combination therapy development.

Main Methods:

  • Development and utilization of a 'bilateral tumor model' in mice, inoculating responsive and unresponsive tumors simultaneously.
  • Characterization of unresponsive tumors based on the presence or absence of systemic immunosuppressive properties (SIP).
  • Investigation of molecular mechanisms, including small molecule inhibition of mitochondrial activation and T cell proliferation, and MHC class I expression.

Main Results:

  • Unresponsive tumors were classified into two groups: SIP-positive and SIP-negative.
  • SIP-positive tumors secreted non-proteinaceous small molecules that suppressed mitochondrial activation and T cell proliferation.
  • SIP-negative B16 tumors evaded immune detection through the downregulation of MHC class I expression, a mechanism distinct from SIP.

Conclusions:

  • The bilateral tumor model effectively stratifies tumors based on distinct non-responsiveness mechanisms to PD-1 blockade.
  • SIP-positive tumor unresponsiveness can be partially addressed by enhancing mitochondrial function, while SIP-negative tumors require different strategies.
  • This stratification approach is vital for developing tailored combination therapies to overcome PD-1 blockade resistance in cancer.
Keywords:
cancer immunotherapycombination therapyenergy metabolismimmune resistanceimmunologyinflammationmouseoxygen consumption ratesystemic immunosuppression

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