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

Alok Kumar,Partha S Chowdhury,Tasuku Honjo,Kenji Chamoto

doi:10.7554/elife.52330

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 mitochondrial activation and T cell proliferation. 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 the 'bilateral tumor model' was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.

Highlights

Cancer immunotherapy using immune checkpoint blockade, antibodies against programmed cell death receptor 1 (PD-1) or its ligand (PD-L1), has made a revolution in cancer treatments as this treatment has durable response even to terminal stage cancers and lesser side-effects compared to the conventional cancer treatments (Brahmer et al, 2010; Couzin-Frankel, 2013; Hodi et al, 2010; Mahoney et al, 2015; Topalian et al, 2015)
We found both the total lymphocytes and the effector memory CD8+ T cells in draining lymph nodes (DLNs) significantly increased in the group of responsive tumors, but did not change in unresponsive tumor-bearing hosts after PD-1 blockade (Figure 1B and C)
One of the biggest issues in PD-1 blockade cancer immunotherapy is how to reduce the rate of unresponsiveness

Summary

Introduction

Cancer immunotherapy using immune checkpoint blockade, antibodies against programmed cell death receptor 1 (PD-1) or its ligand (PD-L1), has made a revolution in cancer treatments as this treatment has durable response even to terminal stage cancers and lesser side-effects compared to the conventional cancer treatments (Brahmer et al, 2010; Couzin-Frankel, 2013; Hodi et al, 2010; Mahoney et al, 2015; Topalian et al, 2015). To further improve its efficacy, we must (i) identify biomarker(s) that predict the responsiveness/unresponsiveness and (ii) develop improved strategy including the combination therapy. For these improvements, we need to understand the mechanism of unresponsiveness to PD-1 blockade therapy. Several studies have worked on the unresponsive mechanism from the immunity side in different models. In one such model, the ‘Cold and Hot tumor hypothesis’, tumors can.

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