Tertiary lymphoid structures (TLS) existence is correlated with favorable prognosis in many types of cancer including non-small cell lung cancer (NSCLC). However, TLS formation and its relationship ...with treatment response remains unknown in NSCLC who received anti-PD-1 antibody plus chemotherapy as the neoadjuvant treatment (neoadjuvant chemoimmunotherapy). Here, we investigate TLS maturation and abundance in resectable NSCLC receiving neoadjuvant treatments. We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from patients with resectable NSCLC (stage II–IIIA) from three cohorts based on treatment: naïve (N=40), neoadjuvant chemoimmunotherapy (N=40), and neoadjuvant chemotherapy (N=41). The TLS in tumor tissues was detected by immunohistochemical staining, and the differences in TLS maturation and abundance among different treatment groups were analyzed, as well as the relationship with pathological response and prognosis of patients. Multiplex immunofluorescence staining was used to explore the features of immune microenvironment. Higher major pathological response (MPR) rate and pathological complete response (pCR) rate were in the neoadjuvant chemoimmunotherapy group than in the neoadjuvant chemotherapy group (MPR: 45.0% vs 17.1%; pCR: 35.0% vs 4.9%). Among the three cohorts, neoadjuvant chemoimmunotherapy-treated NSCLCs displayed highest TLS maturation and abundance. Both the maturation and abundance of TLS were significantly correlated with MPR in both the neoadjuvant chemoimmunotherapy and the chemotherapy group. Patients with high maturation and abundance of TLS exhibited better disease-free survival (DFS) in all the three cohorts. TLS maturation was also an independent predictor for DFS in the neoadjuvant chemoimmunotherapy and treatment naïve group. Multiplex immunohistochemistry analysis using paired biopsy-surgery samples showed increased infiltration of CD8+T cell and decreased infiltration of M1 and M2 macrophages after neoadjuvant chemoimmunotherapy treatment in patients achieving MPR. There were no significant differences in features of immune cell infiltration for those with mature TLS achieving MPR when cross-compared across the three cohorts. These results demonstrate that TLS maturation is associated with MPR and an independent predictor for DFS in resectable neoadjuvant chemoimmunotherapy-treated NSCLC. The induction of TLS maturation may be a potential mechanism of action of neoadjuvant chemoimmunotherapy in resectable NSCLC.
Purpose
Cytokeratin 18 (CK18) is a structural protein that is normally expressed in many single-layer epithelia. Previous studies have indicated that aberrant CK18 expression is associated with ...cancer progression. However, the functions of CK18 in lung cancer have not been fully elucidated. Here, we investigate the roles of CK18 in non-small cell lung cancer (NSCLC).
Methods
CK18 protein expression was evaluated by immunohistochemistry in a lung cancer tissue microarray containing 129 cancer samples, and correlations between CK18 expression and clinicopathological characteristics and prognosis were analyzed. We then studied the effects of CK18 knockdown on cell motility and chemosensitivity in lung cancer cells.
Results
High CK18 expression was detected in 101/129 (78.3 %) lung cancers. CK18 expression was significantly correlated to clinical stage, lymph node metastasis, the number of pathologically positive lymph nodes and recurrence and metastasis. Kaplan–Meier survival analysis showed that CK18 was a prognostic factor for overall survival (
P
= 0.016) and disease-free survival (
P
= 0.014). In addition, CK18 knockdown decreased cell migration and enhanced the sensitivity of lung cancer cells to paclitaxel.
Conclusions
These findings indicate that CK18 plays an important role in lung cancer progression and may be a therapeutic target for NSCLC.
Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The ...objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.
Platinum‐based chemotherapy has been the cornerstone treatment for small cell lung cancer (SCLC) for decades, but no major progress has been made in the past 20 years with regard to overcoming ...chemoresistance. As the cell cycle checkpoint kinase 1 (Chk1) plays a key role in DNA damage response to chemotherapeutic drugs, we explored the mechanisms of acquired drug resistance to the Chk1 inhibitor prexasertib in SCLC. We established prexasertib resistance in two SCLC cell lines and found that DNA copy number, messengerRNA (mRNA) and protein levels of the cell cycle regulator Wee1 significantly correlate with the level of acquired resistance. Wee1 small interfering RNA (siRNA) or Wee1 inhibitor reversed prexasertib resistance, whereas Wee1 transfection induced prexasertib resistance in parental cells. Reverse phase protein microarray identified up‐regulated proteins in the resistant cell lines that are involved in apoptosis, cell proliferation and cell cycle. Down‐regulation of CDK1 and CDC25C kinases promoted acquired resistance in parental cells, whereas down‐regulation of p38MAPK reversed the resistance. High Wee1 expression was significantly correlated with better prognosis of resected SCLC patients. Our results indicate that Wee1 overexpression plays an important role in acquired resistance to Chk1 inhibition. We also show that bypass activation of the p38MAPK signaling pathway may contribute to acquired resistance to Chk1 inhibition. The combination of Chk1 and Wee1 inhibitors may provide a new therapeutic strategy for the treatment of SCLC.
Wee1 up‐regulation is a major and novel mechanism of acquired resistance to Chk1 inhibitors in SCLC. Wee1 expression levels are correlated with resistance levels. Combination of Chk1 and Wee1 inhibitors may overcome this resistance. Combination studies of Chk1 inhibitors such as prexasertib and other agents may lead to synergistic interactions. Combinations with immune check‐point inhibitors might also be of particular interest.
During sepsis, circulating leukocytes are in a hyper inflammatory state, and with the progress of the inflammation, immune cells may become tolerated. Glycolysis and pentose phosphate pathway are ...up-regulated but oxidative phosphorylation is suppressed in hyper inflammatory cells, whereas during immune tolerance, glycolysis is often down-regulated. In this review, we will summarize the changes of cellular metabolic pathways in monocytes and macrophages during sepsis. We also review how the metabolism of glucose, amino acids, and fatty acids affect the function of monocytes and macrophages in sepsis. Current literature indicated that metabolism plays a significant role in regulating the functions of immune cells in sepsis, which might be a potential therapy for sepsis and deserved further research.
Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung ...adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples.
R181C,
G12C and
R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3
regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.
Background
DNA damage repair (DDR) plays a role in the tumorigenesis and progression of lung squamous cell carcinoma (LUSC), but the predictive value of DDR in LUSC has not been fully elucidated.
...Methods
The LUSC datasets were retrieved from the Cancer Genome Atlas databases. Univariate Cox regression and least absolute shrinkage and selection operator regression were integrated to identify critical genes and construct a DDR gene signature. We performed Kaplan–Meier (KM) curve to compare the overall survival (OS) between the two groups based on DDR signature and used the CIBERSORT tool to compare the immune cell composition. Further gene set enrichment analysis (GSEA) was performed on the differential expressed genes.
Result
We established the DDR‐related gene signature on LUSC. KM curve showed the low‐risk group had a better prognosis than the high‐risk group in the training set (p = 0.022673) and the complete set (p = 0.003201). The area under receiver operating characteristic curve for OS was 0.98, 0.96, and 0.97 in the training dataset, testing dataset, and the complete dataset, respectively. The composition of immune cells was different between the high‐ and low‐risk group. The GSEA result suggests that genes of the patients in low‐risk group were mainly enriched in the DNA adducts; drug metabolism‐cytochrome P450, metabolism of xenobiotics by cytochrome P450.
Conclusion
This study identified DDR‐associated potential biomarkers related to overall survival of LUSC and establishes the DDR‐associated gene signature.
This study established a DNA damage repair (DDR)‐related gene signature on lung squamous cell carcinoma with the data from the Cancer Genome Atlas. The DDR signature has prognostic value, and we verify it in training group, testing group, and complete group. Moreover, we have done the Gene Ontology enrichment and gene set enrichment analysis between the high‐ and low‐risk groups defined by signature.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of non-small cell lung cancer (NSCLC). KRAS and EGFR somatic mutations in NSCLC may ...predict resistance and responsiveness to TKI, respectively. Nevertheless, most research to date has been conducted on samples from primary tumors. For many patients with advanced disease, their samples can only be obtained from metastases for test. The molecular characteristics of metastasized tumors may be different from those of primary tumors.
Mutation status of KRAS and EGFR between primary tumors and local lymph node metastases of 80 Chinese patients with NSCLC were analyzed by direct sequencing. Five of them were given gefitinib as neoadjunvant treatment after the EGFR-TKI sensitive mutations were detected in their biopsies of mediastinal lymph nodes metastases. McNemar's test was used to compare the EGFR and KRAS mutation status between primary tumors and corresponding local lymph node metastases. Data evaluation was carried out with SPSS_13.0 statistical software.
Among the 160 samples, one primary tumor and seven metastases were identified with KRAS mutations and 21 primary tumors and 26 metastases were found to have EGFR mutations. KRAS and EGFR mutation status was different between primary tumors and corresponding metastases in 6 (7.5%) and 7 (8.75%) patients, respectively. One patient with no TKI sensitive mutations detected in the primary tumor showed disease progression.
Our results suggest that a considerable proportion of NSCLC in Chinese population showed discrepancy in KRAS and EGFR mutation status between primary tumors and corresponding metastases. This observation may have important implication for the use of targeted TKI therapy in the treatment of NSCLC patients.
Background
Treatment options for Chinese patients with locally advanced or metastatic squamous‐cell non‐small‐cell lung cancer (sqNSCLC) after failure of first‐line chemotherapy are limited. This ...study (ORIENT‐3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second‐line treatment in patients with locally advanced or metastatic sqNSCLC.
Methods
ORIENT‐3 was an open‐label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first‐line platinum‐based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety.
Results
Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval CI, 10.28‐15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47‐9.82) months with docetaxel (hazard ratio HR: 0.74; 95% CI, 0.56‐0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39‐0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86‐25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41‐7.23) months in the docetaxel arm (P = 0.045). Treatment‐related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment.
Conclusions
Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.
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