Taurine enhances the antitumor efficacy of PD-1 antibody by boosting CD8+ T cell function.

The functional state of CD8+ T cells determines the therapeutic efficacy of PD-1 blockade antibodies in tumors. Amino acids are key nutrients for maintaining T cell antitumor immunity. In this study, we used samples from lung cancer patients treated with PD-1 blockade antibodies to assay the amino acids in their serum by mass spectrometry. We found that lung cancer patients with high serum taurine levels generally responded to PD-1 blockade antibody therapy, in parallel with the secretion of high levels of cytotoxic cytokines (IFN-γ and TNF-α). CD8+ T cells cultured with exogenous taurine exhibited decreased apoptosis, enhanced proliferation, and increased secretion of cytotoxic cytokines. High SLC6A6 expression in CD8+ T cells was positively associated with an effector T cell signature. SLC6A6 knockdown limited the function and proliferation of CD8+ T cells. RNA sequencing revealed that SLC6A6 knockdown altered the calcium signaling pathway, oxidative phosphorylation, and T cell receptor signaling in CD8+ T cells. Furthermore, taurine enhanced T cell proliferation and function in vitro by stimulation of PLCγ1-mediated calcium and MAPK signaling. Taurine plus immune checkpoint blockade antibody significantly attenuated tumor growth and markedly improved the function and proliferation of CD8+ T cells in a mouse tumor model. Thus, our findings indicate that taurine is an important driver for improving CD8+ T cell immune responses and could serve as a potential therapeutic agent for cancer patients.

BPIFB2 is highly expressed in "cold" lung adenocarcinoma and decreases T cell chemotaxis via activation of the STAT3 pathway.

BACKGROUND: Studies have shown that patients with lung adenocarcinoma exhibit a poor prognosis, and the overall effective rate of immunotherapy is relatively low. Previous studies reported on the BPIFB2 gene have shown that it participates in immune regulation in gastric cancer; however, the role and mechanisms of BPIFB2 in lung cancer remain unclear. The present study evaluated the mechanism of BPIFB2 in lung adenocarcinoma. METHODS: First, the immune infiltration status of lung adenocarcinoma was analyzed by performing bioinformatics analysis and the BPIFB2 gene was screened. Expression of BPIFB2 in lung adenocarcinoma was studied in vitro, and it was confirmed that BPIFB2 exerted effects on the chemotaxis of tumor cells to T cells. The mechanism was further analyzed and verified via in vivo experiments. Finally, the molecular mechanism of the effect of BPIFB2 on tumor cell chemotaxis T cells was confirmed in clinical specimens. RESULTS: Patients with lung adenocarcinoma presented with different degrees of immune cell infiltration, wherein the tumor tissue exhibiting a low infiltration of CD8+T cells was defined as a cold tumor, demonstrating a high expression of BPIFB2. In vitro experiments revealed that although the knockdown of BPIFB2 exerted no significant effect on the proliferation and apoptosis of tumor cells, it could significantly increase the number of T cells presenting with chemotaxis in lung adenocarcinoma cells, and this might be attributable to a decrease in STAT3 activation and an increase in CCL5 expression after BPIFB2 knockdown. In vivo experiments showed that after BPIFB2 knockdown, the expression of CCL5 increased in tumor cells and the recruitment of T cells increased by tumor cells. It was also confirmed that the expression of BPIFB2 was negatively correlated with CCL5 expression in clinical specimens. CONCLUSION: Our study indicated that BPIFB2 was highly expressed in patients presenting with a cold tumor of lung adenocarcinoma. BPIFB2 knockdown increased the expression of CCL5 and the number of chemotactic CD8+T cells in lung adenocarcinoma. BPIFB2 may thus be considered an important target for immunotherapy.

Nomograms for predicting the overall and cause-specific survival in patients with malignant peripheral nerve sheath tumor: a population-based study.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is extremely rare in soft tissue sarcoma, with a high rate of recurrence and metastasis. Due to its rarity, the epidemiological features and prognostic factors are still uncertain. Moreover, nomograms for patients with MPNST have not been constructed and validated until now. PATIENTS AND METHODS: Patients diagnosed with MPNST between 1973 and 2014 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Survival analysis, machine learning and Lasso regression were used to identify the prognostic factors for overall survival (OS) and cause-specific survival (CSS). Significant prognostic factors were integrated to construct nomograms and then the nomograms were validated externally with a separate cohort from our own institution. RESULTS: A total of 689 patients were included in the training set and 42 patients in the validation set. Multivariate analysis suggested that age, histology, historic stage and chemotherapy were independent prognostic factors for OS and primary site, surgery, historic stage and chemotherapy for CSS. The nomograms based on multivariate models were developed and validated for predicting 3- and 5-year OS and CSS, with a C-index of 0.686 and 0.707, respectively. In the external validation set, the C-index was 0.700 for OS and 0.722 for CSS. CONCLUSION: ICD-O-3 histology, historic stage and chemotherapy were independent prognostic factors for OS and primary site, surgery, historic stage and chemotherapy for CSS. The constructed nomograms could provide individual prediction for MPNST patients and assist oncologists in making accurate survival evaluation.

LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy.

Anti-PD-1 antibody therapy has achieved success in tumor treatment; however, the duration of its clinical benefits are typically short. The functional state of intratumoral CD8+ T cells substantially affects the efficacy of anti-PD-1 antibody therapy. Understanding how intratumoral CD8+ T cells change will contribute to the improvement in anti-PD-1 antibody therapy. In this study, we found that tumor growth was not arrested after the late administration of anti-PD-1 antibody and that the antitumor function of CD8+ T cells decreased with tumor progression. The results of the RNA sequencing of CD8+ T cells infiltrating the tumor site on days 7 and 14 showed that the cell adhesion molecule Lymphocyte Function-associated Antigen-1 (LFA-1) participates in regulating the antitumor function of CD8+ T cells and that decreased LFA-1 expression in intratumoral CD8+ T cells is associated with tumor progression. By analyzing the Gene Expression Omnibus (GEO) database and our results, we found that the antitumor function of intratumoral CD8+ T cells with high LFA-1 expression was stronger. The formation of immune synapses is impaired in Itgal-si CD8+ T cells, resulting in decreased anti-tumor function. LFA-1 expression in intratumoral CD8+ T cells is regulated by the IL-2/STAT5 pathway. The combination of IL-2 and anti-PD-1 antibody effectively enhanced LFA-1 expression and the antitumor function of intratumoral CD8+ T cells. The adoptive transfer of OT-1 T cells overexpressing LFA-1, STAT5A, or STAT5B resulted in higher antitumor function, deferred tumor growth, and prolonged survival. These findings indicate that LFA-1-mediated immune synapse acts as a regulator of the antitumor function of intratumoral CD8+ T cells, which can be applied to improve anti-PD-1 antibody therapy.

Potential non-invasive biomarkers in tumor immune checkpoint inhibitor therapy: response and prognosis prediction.

Immune checkpoint inhibitors (ICIs) have dramatically enhanced the treatment outcomes for diverse malignancies. Yet, only 15-60% of patients respond significantly. Therefore, accurate responder identification and timely ICI administration are critical issues in tumor ICI therapy. Recent rapid developments at the intersection of oncology, immunology, biology, and computer science have provided an abundance of predictive biomarkers for ICI efficacy. These biomarkers can be invasive or non-invasive, depending on the specific sample collection method. Compared with invasive markers, a host of non-invasive markers have been confirmed to have superior availability and accuracy in ICI efficacy prediction. Considering the outstanding advantages of dynamic monitoring of the immunotherapy response and the potential for widespread clinical application, we review the recent research in this field with the aim of contributing to the identification of patients who may derive the greatest benefit from ICI therapy.

Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis.

Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.

Immune Profiling Reveals Molecular Classification and Characteristic in Urothelial Bladder Cancer.

Urothelial bladder cancer (UBC) is the most common malignant tumor of the urinary system. Most patients do not benefit from treatment with immune checkpoint inhibitors, which are closely associated with immune profiling in the context of UBC. Therefore, we aimed to characterize the immune profile of UBC to identify different immune subtypes that may influence therapy choice. We identified four subtypes of UBC based on immune profiling including immune ignorant, cold tumor, immune inactive, and hot tumor. After excluding the cold tumor subtype because of its unique pathology distinct from the other types, a high correlation between patient survival and immune characteristics was observed. Most immune cell types had highly infiltrated the hot tumor subtype compared to other subtypes. Interestingly, although immune cells infiltrated the tumor microenvironment, they exhibited an exhaustion phenotype. CCL4 may be the key molecule functioning in immune cell infiltration in the hot tumor subtype. Moreover, neutrophils may function as an important suppressor in the tumor microenvironment of the immune ignorant and immune inactive subtypes. Furthermore, different tumor-intrinsic signaling pathways were involved in immune cell infiltration and exclusion in these four different subtypes. Immune profiling could serve as a prognostic biomarker for UBC, and has potential to guide treatment decisions in UBC. Targeting tumor-intrinsic signaling pathways may be a promising strategy to treat UBC.

Identification and characterization of prognosis-related genes in the tumor microenvironment of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the main pathological subtype of esophageal cancer with high incidence and mortality. Immune and stromal cells in the tumor microenvironment (TME) profoundly affect the development of ESCC. METHODS: In this study, we used the ESTIMATE algorithm to calculate the immune and stromal scores of ESCC samples in The Cancer Genome Atlas (TCGA) database. Next, we used the R package limma to identify differentially expressed genes (DEGs) from high- versus low-immune/stromal score groups and these DEGs were further utilized to analyze the functional annotations, protein-protein interaction (PPI) networks and overall survival of patients with ESCC. Finally, we identified the biological roles of core gene C3AR1 in the TME of ESCC using the TCGA database and in vitro experiments. RESULTS: We obtained the immune and stromal scores of ESCC samples and further evaluated the impact of these scores on the prognosis and clinical parameters of patients with ESCC. Next, we identified 410 DEGs from high- versus low-immune/stromal score groups and to gain better understanding of the biological functions and characteristics of DEGs. Among these DEGs, 69 were correlated with the overall survival of patients with ESCC and C3AR1 was identified as a core gene for the regulation of most genes in the network. We found that C3AR1 was positively correlated with M2 macrophages and immune inhibitory molecules (T-cell immunoglobulin and mucin domain 3 (TIM-3), programmed cell death-1 (PD-1)), but not with M1 macrophages. We also observed a higher expression of CD163 and CD206, which were the markers for M2 macrophages in the TLQP-21 TFA (the agonist of C3AR1)groups than in the control groups. CONCLUSION: Based on the ESTIMATE algorithm, we obtained and characterized prognosis-related genes in the TME of ESCC samples from the TCGA database. We have further revealed that C3AR1 may cause an immunosuppressive microenvironment by affecting the polarization of macrophages to M2 phenotype and lead to the progression of ESCC, which indicates that C3AR1 may be a potential target for immunotherapy.