Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

Abstract

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Mitochondrial Signaling Pathways Associated with DNA Damage Responses

“…PD-L1/PD-1 blockade by AMPK activation significantly enhances cancer immunotherapy [ 126 , 127 ]. Pink1 regulates mitochondrial localization of PD-L1 for its degradation via mitophagy [ 128 ].…”

Drug co-administration in the tumor immune microenvironment of Hepatocellular carcinoma

“…Paclitaxel (PTX) increased ATAD3A expression, which disrupts the stability of PD-L1 by inhibiting PINK1-dependent mitosis. The results of preclinical studies further demonstrated that targeting ATAD3A could reset a favorable anti-tumor immune microenvironment and improve the efficacy of ICI combination therapy, increasing the effectiveness of ICI plus PTX combination therapy [30] .…”

Identification of ATAD3A as a key regulator in non‐small cell lung cancer by promoting STAT3‐induced cell proliferation and tumor angiogenesis

“…Furthermore, ATAD3A is also involved in the sensitivity and resistance of tumor drugs. For instance, high levels of ATAD3A expression can reduce the sensitivity of tumor cells to certain chemotherapy drugs, which in turn can impact the effectiveness of tumor treatment 12 . However, the role and regulation mechanisms of ATAD3A in LUAD is still lack of further understanding and research, and its impact on tumor microenvironment is also unknown.…”

“…For instance, high levels of ATAD3A expression can reduce the sensitivity of tumor cells to certain chemotherapy drugs, which in turn can impact the effectiveness of tumor treatment. 12 However, the role and regulation mechanisms of ATAD3A in LUAD is still lack of further understanding and research, and its impact on tumor microenvironment is also unknown. Therefore, further studies of ATAD3A and the effect of its specific inhibitors in LUAD will help understand its mechanism and potential application.…”