Human leukocyte antigen class II-based immune risk model for recurrence evaluation in stage I–III small cell lung cancer

BackgroundImmunotherapy has revolutionized therapeutic patterns of small cell lung cancer (SCLC). Human leukocyte antigen class II (HLA class II) is related to antitumor immunity. However, the implications of HLA class II in SCLC remain incompletely understood.Materials and methodsWe investigated the expression patterns of HLA class II on tumor cells and tumor-infiltrating lymphocytes (TILs) by immunohistochemistry staining and its association with clinical parameters, immune markers, and recurrence-free survival (RFS) in 102 patients with stage I–III SCLC with radical surgery. Additionally, an HLA class II-based immune risk model was established by least absolute shrinkage and selection operator regression. With bioinformatics methods, we investigated HLA class II-related enrichment pathways and immune infiltration landscape in SCLC.ResultsHLA class II on tumor cells and TILs was positively expressed in 9 (8.8%) and 45 (44.1%) patients with SCLC, respectively. HLA class II on TILs was negatively associated with lymph node metastasis and positively correlated with programmed death-ligand 1 (PD-L1) on TILs (p<0.001) and multiple immune markers (CD3, CD4, CD8, FOXP3; p<0.001). Lymph node metastasis (OR 0.314, 95% CI 0.118 to 0.838, p=0.021) and PD-L1 on TILs (OR 3.233, 95% CI 1.051 to 9.95, p=0.041) were independent predictive factors of HLA class II on TILs. HLA class II positivity on TILs prompted a longer RFS (40.2 months, 95% CI 31.7 to 48.7 vs 28.8 months, 95% CI 21.4 to 36.3, p=0.014). HLA class II on TILs, PD-L1 on TILs, CD4, and FOXP3 were enrolled in the immune risk model, which categorized patients into high-risk and low-risk groups and had better power for predicting the recurrence than tumor stage. Pathway enrichment analyses showed that patients with high HLA class II expression demonstrated signatures of transmembrane transportation, channel activity, and neuroactive ligand–receptor interaction. High-risk SCLC patients had a higher proportion of T follicular helper cells (p=0.034) and a lower proportion of activated memory CD4-positive T cells (p=0.040) and resting dendritic cells (p=0.045) versus low-risk patients.ConclusionsHLA class II plays a crucial role in tumor immune microenvironment and recurrence prediction. This work demonstrates the prognostic and clinical values of HLA class II in patients with SCLC.

Activating Killer-cell Immunoglobulin-like Receptors are associated with the severity of COVID-19

Background Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. Here we investigate the role of Killer-cell Immunoglobulin-like receptor (KIR)/Human Leukocyte Antigen Class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. Methods KIR and HLA-I genotyping and NK cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 non-infected controls. Results NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4 low CD16 low CD226 low CD56 high TIGIT high NKG2A high), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe than mild/moderate patients and controls (83.7%, 55.7% and 36.2%, p&lt;7.7x10 -9). In mild/moderate patients HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared to patients with other HLA-B*15 subtypes and non-infected controls (90.9%, 42.9% and 47.3%, p&lt;0.002, Pc=0.022). This strongly suggests that HLA-B*15:01 specifically presenting SARS-CoV-2 peptides could form a neo-ligand interacting with KIR3DS1. Similarly, a putative neo-ligand for KIR2DS4 could arise from other HLA-I molecules presenting SARS-CoV-2 peptides expressed on infected/activated lung antigen presenting cells. Conclusions Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/Ligand interactions associated to disease severity.