Dataset Information

Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma.

ABSTRACT:

Background

Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy.

Objectives

The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC).

Methods

Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining.

Results

HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8⁺LAG3⁺ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy.

Conclusions

CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.

SUBMITTER: Hsu CL

PROVIDER: S-EPMC8339511 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThis study aimed to evaluate safety and efficacy of programmed death-1 (PD-1) inhibitor sintilimab plus tyrosine kinase inhibitors (TKI) in a real-word cohort of patients with unresectable hepatocellular carcinoma (uHCC).MethodsA total of 60 patients treated with sintilimab plus TKI between February 2019 and December 2019 were enrolled. Radiological response was recorded by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every 6-12 weeks after treatment initiation. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC-specific modified RECIST (mRECIST).ResultsAs of the data cutoff on September 30st, 2020, the median duration of follow-up was 10.4 (4.3-23.9) months. The objective response rate (ORR) and disease control rate (DCR) were 36.7% (95% CI: 24.9-48.5%), 81.7% (95% CI: 71.9-91.5%) according to the RECIST 1.1, and 52.8% (95% CI: 39.1-66.5%), 83.0% (95% CI: 73.2-93.8%) according to mRECIST criteria. Among 36 HCC patients with multinodular HCC or locally-advanced HCC with portal vein tumor thrombus (PVTT), 14 patients received one session of transarterial chemoembolization (TACE) within 1 month before or after the combinational systemic therapies, and the rest 22 patients did not receive any local regional therapies. After propensity score matching, patients from the TACE group tended to have a longer PFS (median, 10.1 vs. 9.1 months, P=0.73) than those from the non-TACE group but without significant differences. A total of 8 patients received surgical resection after the combined systemic therapies and 3 patients achieved pathological CR. No recurrence or metastasis was observed in 6 patients. A total of 46 (76.7%) patients reported adverse event (AE) with any grade and 8 (13.3%) patients discontinued the combination therapy due to grade 3/4 severe adverse events.ConclusionsPD-1-targeted immunotherapy sintilimab plus TKIs exhibited promising efficacy with tolerable toxicity in unresectable HCC. The addition of TACE to the combined systemic therapies also resulted in a favorable tumor control and safety. For select responders, surgical resection might be a choice for radical treatment.