Overcoming immunotherapy resistance in hepatocellular carcinoma by targeting myeloid IL-8/CXCR2 signaling
Bibliographic record
Abstract
Durable responses to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) was performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a phase 2 clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2, mainly derived from immunosuppressive myeloid-derived suppressor cells (MDSCs). In particular, the high circulating IL-8 level was strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of the IL-8/CXCR2 pathway significantly abrogated MDSC trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcomes also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response but it also provides a proof of concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".