Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Abstract

Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

“…We further show that this metabolic manipulations improves treatment outcome upon PD-1 blockade, which is in agreement with the synergistic effect of anti-PD-1 treatment with chemicals that activate mitochondrial functions (Chamoto et al, 2017). Similarly, other studies show that memory CD8 + T cells, which prefer FAO and OXPHOS for energy production, more efficiently slow tumor progression than effector cells (Crompton et al, 2015; Sukumar et al, 2013).…”

PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression

“…These data suggest that PD-L1 blockade therapy may require T cell activation/ reactivation both inside and outside the tumor (Figure 3, C-E). Consistent with our observations, a recent study shows that surgical dLN ablation completely abrogates the antitumor effects of PD-L1 blockade (34). Together, our data suggest that the impact of PD-L1 blockade outside the tumor needs to be revisited.…”

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

“…In contrast to TIL in a melanoma model (26), ccRCC CD8 TIL retained or increased overall mitochondrial mass and appeared to also express PGC1α and electron transport components at normal levels. Mitochondrial mass was also maintained in TIL from a colorectal carcinoma model, although uncoupling of mitochondrial electron transport was proposed to increase T cell function (51). In ccRCC CD8 TIL, however, mitochondria produced ROS and appeared highly fragmented and in condensed configuration relative to normal healthy CD8 T cell mitochondria.…”