Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is considered a novel anti-tumor target comparable to programmed cell death 1 ligand 1(PD-L1). However, little is known about Siglec-15. Our study aims to understand its expression signature, prognosis value, immune infiltration pattern, and biological function using multi-omic bioinformatics from public databases and verify them in lung cancer patients. Integrated analysis of The Cancer Genome Atlas and Genotype-Tissue Expression portals showed Siglec-15 was overexpressed across cancers. Genetic and epigenetic alteration analysis was performed using cBioportal and UALCAN, showed Siglec-15 was regulated at the genetic and epigenetic levels. Survival estimated using Kaplan-Meier plotter indicated high Siglec-15 expression correlated with favorable or unfavorable outcomes depending on the different type and subtype of cancer. Components of immune microenvironment were analyzed using CIBERSORT, and the correlation between immune cells and Siglec-15 was found to be distinct across cancer types. Based on Gene Set Enrichment Analysis, Siglec-15 was implicated in pathways involved in immunity, metabolism, cancer, and infectious diseases. Lung cancer patients with positive Siglec-15 expression showed significantly short survival rates in progressionfree survival concomitant with reduced infiltration of CD20 + B, and dendritic cells by immunohistochemistry. Quantitative real-time PCR results indicated the overexpression of Siglec-15 was correlated with activation of the chemokine signaling pathway. In conclusion, Siglec-15 could serve as a vital prognostic biomarker and play an immune-regulatory role in tumors. These results provide us with clues to better understand Siglec-15 from the perspective of bioinformatics and highlight the importance of Siglec-15 in many types of cancer.

Background: A small proportion of patients with non-small cell lung cancer (NSCLC) experience objective clinical benefit after neoadjuvant programmed cell death 1 (PD-1) blockade. A neoadjuvant therapeutic regimen combining immune checkpoint blockade with chemotherapy might improve the treatment effect, but such a regimen has not been tested in patients with resectable stage IIIA/IIIB NSCLC.Methods: A retrospective study of 35 patients with resectable stage IIIA and IIIB NSCLC who were treated with neoadjuvant chemoimmunotherapy (NCIO) was performed. Patients were evaluated for pathological complete response (pCR), major pathologic response (MPR), safety, and feasibility. The correlations of pathologic response with various clinical factors were studied to identify predictors of pathological response.Results: NCIO was associated with few immediate adverse events. NCIO did not delay planned surgery and led to a pCR rate of 51.43% and an MPR rate of 74.29% for the primary tumor. No association was observed between programmed death-ligand 1 (PD-L1) expression before NCIO and the pathologic response (Pearson's r=−0.071; P=0.685). However, a significant difference was observed in pathological response in patients with intracavitary and extracavitary tumors (P<0.05). Patients with intracavitary type had a higher pCR (76.47% vs. 31.58%) and MPR (100% vs. 50.00%) rate than patients with extracavitary type (Pearson's r=0.7280; P=0.0009).Conclusions: NCIO was associated with few side effects, did not delay surgery, and achieved a pCR in 51.43% and MPR in 74.29% of resected tumors. No significant correlation was found between pathologic response and PD-L1 expression. While the intracavitary and extracavitary tumors type T was predictive of the pathological response to NCIO.

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In current studies, the influence of tumor immune microenvironment on tumorigenesis and tumor progression has been widely explored. In the present study, we investigated the expression and significance of high mobility group box 1 (HMGB1), HMG nucleosome-binding protein 1 (HMGN1), the receptor programmed cell death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC). We explored whether HMGB1 and HMGN1 take part in recruiting T cells to HNSCC microenvironment. Furthermore, we assessed the prognostic value of HMG proteins, TILs, and PD-1/PD-L1 in postoperative patients. Tumor tissue sections were collected from 81 cases of patients with resectable HNSCC. All patients' information was integrated with clinical and pathological records, as well as follow-up data. We used immunohistochemistry to examine the subcellular localization and expression levels of HMGB1 and HMGN1, as well as tumor CD3+, CD8+, FOXP3+ lymphocyte infiltration, and the expression of immune inhibiting molecules PD-1/PD-L1. Results showed that there was no significant difference in the number of CD8+ and FOXP3+ T cells between the two groups with or without HMGB1 cytoplasmic expression in tumor tissues. The number of CD3+ T cells in HMGB1 cytoplasmic expression group (339.39 ± 230.76) was more than that in group without HMGB1 cytoplasmic expression (233.30 ± 230.91, P < 0.05). The number of CD3+, CD8+, and FOXP3+ T cells in HMGN1 cytoplasmic expression group [400.74 ± 224.04, 158.10 ± 112.10, 36.00(15.00, 69.00)] was more than that in group without HMGN1-cytoplasmic expression [222.84 ± 217.78, P < 0.01; 105.10 ± 108.25, P < 0.05; 13.00(6.75, 32.25), P < 0.01]. The positive rates of PD-1 and PD-L1 in tumor tissues were 29.6 and 67.9%, respectively. Multivariate analysis suggested that tumor expression of PD-L1 was an independent prognostic factor and PD-L1 overexpression indicated a poor overall survival (OS) and disease-free survival (DFS). Taken together, we concluded that HMGB1 and HMGN1 secreted by cancer cells may relate to recruitment of tumor infiltrating lymphocytes (TILs) in HNSCC. PD-1/PD-L1 axis, rather than HMG proteins or CD8+ tumor-infiltrating lymphocytes, has a critical role in tumor immune microenvironment and could predict the outcome of HNSCC patients who received surgical resection.

TNM stage is not enough to accurately predict the prognosis of patients with non-small cell lung cancer (NSCLC). This study aimed to establish the Immunoscore (IS) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), separately, and propose a new staging system in NSCLC. We used the multiplex fluorescent immunohistochemistry (mIHC) technology to detect 17 immune biomarkers of 304 patients with NSCLC. The LASSO-COX regression model was used to establish the IS NSCLC in the training cohorts. The IS NSCLC was then validated in the validation cohort. The constructed IS LUAD contained three immune features: CD4 + CD73 + core of tumor (CT) , PD-L1 + CT , and IDO + invasive margin (IM). IS LUSC also contained two immune features: CD8 + CD39 − CD73 − CT , CD8 + Tim-3 + IM. In the training cohort, significant prognostic differences were found upon comparing low-IS NSCLC patients with high-IS NSCLC patients. For LUAD, the 5-y disease-free survival (DFS) rates were 54.7% vs. 8.1% and the 5-y overall survival (OS) rates were 82.4% vs. 36% (all P< .0001). For LUSC, the 5-y DFS rates were 74.0% vs. 14.7% and the 5-y OS rates were 78.2% vs. 17.6% (all P< .0001). Multivariate analyses indicated that IS NSCLC was an independent indicator for prognosis. Finally, we combined IS NSCLC with clinicopathological factors to establish a TN-I staging system and two nomogram models for clinical use. The TN-I stage had better prediction accuracy than TNM stage. The newly established IS LUAD and IS LUSC were completely different, and both were excellent indicators for the prognostic prediction. The TN-I stage could effectively improve prognostic accuracy and facilitate clinical application.