Cell Death Dis. 2025 Mar 4;16(1):152. doi: 10.1038/s41419-025-07471-w.

题目：

High baseline levels of PD-L1 reduce the heterogeneity of immune checkpoint signature and sensitize anti-PD1 therapy in lung and colorectal cancers

作者：

Peng Fan^1,2,3,4,9, Ziwei Qi^1,9, Zhenhua Liu^5,6,9, Shanshan Wang¹, Ying Wang¹, Jiajie Kuai⁷, Naidong Zhang^1,3, Wei Xu⁸, Songbing Qin^{5 *} , Eleonora Candi ³ and Yuhui Huang ^{1,2,4 *}

单位：

1 Cyrus Tang Medical Institute, State Key Laboratory of Radiation Medicine and Prevention, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.

2 Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, China.

3 Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Rome, Italy.

4 National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou, China.

5 Department of Radiotherapy, the First Affiliated Hospital of Soochow University, Suzhou, China.

6 Department of Radiotherapy, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, China.

7 Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, China.

8 New Drug Biology and Translational Medicine, Innovent Biologics Inc., Suzhou, China.

9 These authors contributed equally: Peng Fan, Ziwei Qi, Zhenhua Liu.

摘要：

Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon g, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratication and prediction performance in the clinic.

During early tumorigenesis, immune checkpoints are usually expressed at relatively low levels (HIS-low), thus sensitive to ICB therapy. Following tumor progression, the tumor microenvironment (TME) becomes increasingly immune suppressive to evade host immunosurveillance. This process involves two potential mechanisms: a stochastic upregulation of multiple immune checkpoints, leading to HIS-high and resistance to ICB therapy (Majority), or a selective overexpression of a few pivotal immune checkpoints while maintaining others at lower levels (Minority). Therefore, the elevated expression of key immune checkpoints reduces the HIS in large tumors compared to small tumors, rendering those large tumors sensitive to blocking the predominant immunosuppressive signal in the TME.