A tumor cornification and immune-infiltration-based scheme for anti-PD-1 plus chemotherapy response in advanced
Minlin Jiang1, Jiya Sun2, Congli Hu1
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China; Medical School, Tongji University, Shanghai 200433, China.
Background:
Anti-PD-1 immunotherapy plus chemotherapy (combo) exhibits significantly prolonged survival for squamous cell lung cancer (LUSC). An exploration of predictive biomarkers is still needed.
Methods:
High-throughput RNA sequencing (RNA-seq) of 349 LUSC samples from the randomized, multi-center, phase 3 trial ORIENT-12 (ClinicalTrials.gov: NCT03629925) was conducted for biomarker discovery, followed by flow cytometry and multiplex immunohistochemistry (mIHC) in additional clinical cohorts, and in vitro experiments were performed for verification.
Results:
A high abundance of activated CD8+ T and CD56bright natural killer (NK) cells benefited patients' outcomes (progression-free survival [PFS]; overall survival [OS]) with combo treatment. Tumor cornification level remarkably affected the infiltration of the two crucial immune cells. Thus, a novel scheme of LUSC immune infiltration and cornification characterization-based classification (LICC) was established for combo efficacy prediction. Patients who received combo treatment achieved significant PFS improvements in LICC1 (hazard ratio [HR] = 0.43, 95% confidence interval [CI]: 0.25-0.75, p = 0.0029) and LICC2 (HR = 0.32, 95% CI: 0.17-0.58, p = 0.0002) subtypes but not in the LICC3 subtype (HR = 0.86, 95% CI: 0.60-1.23, p = 0.4053). Via single-cell RNA-seq analysis, the tumor cornification signal was mainly mapped to SPRR3+ tumor cells, whose relationships with activated CD8+ T or CD56bright NK cells were verified using flow cytometry and mIHC. Our data suggest that SPRR3+ tumor cells might evade immune surveillance via the CD24-SIGLEC10 (M2 macrophage) axis to maintain a suppressive tumor microenvironment.
Conclusions:
Tumor cornification greatly impacts immune infiltration, and the LICC scheme may guide clinical medication of anti-PD-1+chemo treatment in patients with LUSC.
Funding:
The study was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, Shanghia Multidisplinary Cooperation Building Project for Diagnosis and Treatment of Major Disease, and Innovent Biologics, Inc.
