Uncovering immune checkpoint heterogeneity in oral squamous cell carcinoma using single cell RNA-sequencing data highlights three subgroups of patients with distinct immune phenotypes.

OBJECTIVES: In head and neck squamous cell carcinoma (HNSCC), PD-1/PD-L1 inhibitors remain inefficient in most patients, which points to the need for better characterization of immune checkpoint (ICP) molecule expression. MATERIAL AND METHODS: We evaluated the expression of 22 ICP ligands (ICPL) in 2,176 malignant cells from 10 patients in a public single-cell RNA-sequencing dataset and in two cohorts of HNSCC patients for which gene expression data are available. RESULTS: Based on ICPL expression, malignant cells formed three distinct clusters characterized either by a strong expression of ICPL together with an immune phenotype linked to IFN-γ response (cluster 1) or by a weak ICPL expression and little response to IFN-γ (clusters 2 and 3). Malignant cells from cluster 3 showed a high PD-L1 expression associated with NRF2 signature. The relevance of 3 groups of patients, i.e "high ICPL/high IFN-γ", "low ICPL/low IFN-γ" or "low ICPL/low IFN-γ/high PD-L1" was confirmed in a cohort of 259 OSCC whole tumor samples from TCGA and in the CLB-IHN cohort including patients treated with PD1/PD-L1 inhibitors. The heterogeneous expression of ICPL among patients' malignant cells was associated with immunologically distinct microenvironments, evaluated with the "hot/cold" and the Tumor microenvironment (TME) classification. Finally, the "low ICPL/low IFN-γ/high PD-L1" group 3 displayed a poor prognosis in the TCGA cohort. CONCLUSION: Hence, the global picture of ICPL gene expression in malignant cells from HNSCC patients may contribute to the broader issue of improving immunotherapy strategies though a better stratification of patients and the design of new treatment combinations.

Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

INTRODUCTION: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. METHODS: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. RESULTS: Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. CONCLUSION: This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.