Improving cancer immunotherapy by targeting IL-1.

Interleukin-1 (IL-1) is an inflammatory cytokine associated with tumor invasiveness and metastasis. We recently found that baseline IL-1 in melanomas promoted resistance to immunotherapy by creating an immunosuppressive tumor microenvironment and that IL-1 produced in response to CD40 agonist also induced resistance to therapy. Here, we discuss how naturally occurring and immunotherapy-induced IL-1 in tumors causes immune suppression and resistance to immunotherapy, and we discuss targeting the IL-1 pathway to enhance the efficacy of immunotherapy.

IL-1α Mediates Innate and Acquired Resistance to Immunotherapy in Melanoma.

Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.

HOXA9 rs3801776 G>A polymorphism increases congenital talipes equinovarus risk in a Chinese population.

BACKGROUND: Congenital talipes equinovarus (CTEV) is the most common congenital deformity in children, and muscular dysplasia plays a potential role in the etiology of CTEV. Notably, previous studies have found that HOXA9 rs3801776 and TPM2 rs2025126 genetic polymorphisms play important roles in regulating muscle development in Caucasian children; however, there is a lack of investigations conducted in Chinese children. METHODS: We conducted a hospital-based, case-control study of 189 children with CTEV and 457 CTEV-free children aiming to examine the associations between these two polymorphisms and CTEV susceptibility. The rs3801776 (G>A) and rs2025126 (G>A) polymorphisms were genotyped using TaqMan. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the associations between the selected polymorphisms and CTEV susceptibility. RESULTS: We found that rs3801776A was associated with increased CTEV risk (GA versus GG: adjusted OR = 1.81, 95% CI = 1.22-2.69, p = 0.0031; AA versus GG: adjusted OR = 2.19, 95% CI = 1.28-3.73, p = 0.0041; GA/AA versus GG: adjusted OR = 1.89, 95% CI = 1.29-2.76, p = 0.0010). In a stratified analysis, the risk effect of rs3801776 GA/AA was observed in both unilateral and bilateral patients. CONCLUSIONS: The present study suggests that the rs3801776 G>A polymorphism is associated with CTEV risk in Chinese children; however, this conclusion should be validated in larger studies.

Stromal Modulation Reverses Primary Resistance to Immune Checkpoint Blockade in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC. We demonstrate here effective stromal modulation by a polymeric micelle-based nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine, abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel, abbreviated as PTX). The formulation, M-CPA/PTX, modulated the PDAC stroma by increasing the intratumoral vasculature density, which then promoted the tumor infiltration by cytotoxic CD8+ T cells without depletion of tumor-restraining α-smooth muscle action-positive fibroblasts and type I collage in the stroma. The combination of M-CPA/PTX and the PD-1 checkpoint blockade significantly prolonged animal survival in an orthotopic murine PDAC model as well as a genetically engineered mouse model of PDAC. The superior antitumor efficacy was mediated by enhanced tumor infiltration of CD8+ T cells without concomitant infiltration of suppressive regulatory T cells or myeloid-derived suppressor cells and by the coordinated action of PTX and interferon-gamma. Our results demonstrate that stroma-modulating nanoformulations are a promising approach to potentiate immune checkpoint blockade therapy of pancreatic cancer.

Peptide Vaccine Formulation Controls the Duration of Antigen Presentation and Magnitude of Tumor-Specific CD8+ T Cell Response.

Despite remarkable progresses in vaccinology, therapeutic cancer vaccines have not achieved their full potential. We previously showed that an excessively long duration of Ag presentation critically reduced the quantity and quality of vaccination-induced T cell responses and subsequent antitumor efficacy. In this study, using a murine model and tumor cell lines, we studied l-tyrosine amino acid-based microparticles as a peptide vaccine adjuvant with a short-term Ag depot function for the induction of tumor-specific T cells. l-Tyrosine microparticles did not induce dendritic cell maturation, and their adjuvant activity was not mediated by inflammasome activation. Instead, prolonged Ag presentation in vivo translated into increased numbers and antitumor activity of vaccination-induced CD8+ T cells. Indeed, prolonging Ag presentation by repeated injection of peptide in saline resulted in an increase in T cell numbers similar to that observed after vaccination with peptide/l-tyrosine microparticles. Our results show that the duration of Ag presentation is critical for optimal induction of antitumor T cells, and can be manipulated through vaccine formulation.

Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy.

Anticancer vaccination is a promising approach to increase the efficacy of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA registration trial for anti-CTLA-4 therapy (ipilimumab) revealed a complete lack of benefit of adding vaccination with gp100 peptide formulated in incomplete Freund's adjuvant (IFA). Here, using a mouse model of melanoma, we found that gp100 vaccination induced gp100-specific effector T cells (Teffs), which dominantly forced trafficking of anti-CTLA-4-induced, non-gp100-specific Teffs away from the tumor, reducing tumor control. The inflamed vaccination site subsequently also sequestered and destroyed anti-CTLA-4-induced Teffs with specificities for tumor antigens other than gp100, reducing the antitumor efficacy of anti-CTLA-4 therapy. Mechanistically, Teffs at the vaccination site recruited inflammatory monocytes, which in turn attracted additional Teffs in a vicious cycle mediated by IFN-γ, CXCR3, ICAM-1, and CCL2, dependent on IFA formulation. In contrast, nonpersistent vaccine formulations based on dendritic cells, viral vectors, or water-soluble peptides potently synergized with checkpoint blockade of both CTLA-4 and PD-L1 and induced complete tumor regression, including in settings of primary resistance to dual checkpoint blockade. We conclude that cancer vaccine formulation can dominantly determine synergy, or lack thereof, with CTLA-4 and PD-L1 checkpoint blockade therapy for cancer.

Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy.

Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.

Should tumor with direct adjacent lobe invasion (Tdali) be assigned to T2 or T3 in non-small cell lung cancer: a meta-analysis.

BACKGROUND: The staging of tumor with direct adjacent lobe invasion (Tdali) or interlobar invasion pleural 3 (ILI PL3) in TNM system of non-small cell lung cancer (NSCLC) is still in controversy. We conducted a meta-analysis to compare the prognosis of Tdali with T2 or T3 disease. METHODS: PubMed and Embase were searched for relevant studies. Ln hazard ratio (HR) and its standard error (SE) of each study were estimated in the comparison of overall survival (OS) between Tdali and T2 or T3 respectively. Forest plots were used to show the combined HRs. RESULTS: The meta-analysis for comparison of OS of Tdali and T2 or T3 disease both showed a significant HR [Tdali versus T2, 1.39 (1.21, 1.61), P<0.000, Tdali versus T3, 0.73 (0.57, 0.93), P=0.01]. Comparisons of OS of Tdali specified to T2 (Tdali-T2) and that of all patients of T2 or T3 disease also both showed significant HRs [Tdali-T2 versus T2, 1.44 (1.23, 1.69), P<0.000, Tdali-T2 versus T3, 0.77 (0.64, 0.94), P=0.008]. When only analyzing the patients with N0 status, those with Tdali-T2N0 compared to the T2N0 group had a HR of 1.79 (1.37, 2.34) (P<0.000). For those with Tdali-T2N0 compared to the T3N0 group, the HR was 0.98 (0.71, 1.35) (P=0.91). CONCLUSIONS: Our meta-analysis showed that the prognosis of Tdali is poorer than T2 disease but similar to T3 disease after controlled for T and N status. We suggest that Tdali should be considered to be upgraded to T3. Our work challenges the current staging system regarding staging of Tdali, which might be important evidence of future revision of Tdali staging. As the malignancy of Tdali has been underrated till now, more attention needs to be drawn to proper treatment of Tdali patients.

Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis.

Tumor-associated macrophages (TAMs) are important components of cancer microenvironment. In the present study, we searched PubMed, Embase, Cochrane library and Web of Science to perform a meta-analysis of 20 studies including a total of 2,572 non-small cell lung cancer (NSCLC) patients, in order to determine the association between TAMs and NSCLC prognosis. The combined hazard ratio (HR) of 9 studies showed that the density of total CD68+ TAMs in the tumor islet and stroma was not associated with overall survival (OS) of the patients. However, the pooled HR of 4 studies showed that high density of CD68+ TAMs in the tumor islet predicted better OS, while the pooled HR of 6 studies showed that high density of CD68+ TAMs in the tumor stroma was associated with poor OS. A high islet/stroma ratio of CD68+ TAMs was associated with better OS. A high density of M1 TAMs in the tumor islet was associated with better OS, while a high density of M2 TAMs in the tumor stroma predicted poor OS. These findings suggest that, although the density of total CD68+ TAMs is not associated with OS, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC.

Unusual cause of massive hemothorax: spontaneous rupture of nonfunctioning mediastinal paraganglioma.

Mediastinal paraganglioma is a rare neurogenic tumor with a hypervascular feature. The spontaneous rupture of mediastinal paraganglioma is an unusual cause of massive hemothorax. Here we present a case of 39-year-old man with massive hemothorax due to the spontaneous rupture of a mediastinal paraganglioma. The man underwent successful resection of tumor and had an uneventful recovery. To our knowledge, this is the first reported case of spontaneous rupture of nonfunctioning mediastinal paraganglioma.

Simultaneous thoracoscopic resection for coexisting pulmonary and thymic lesions.

BACKGROUND: The management of synchronous thymic and pulmonary lesions remains a challenge due to the lack of case series and surgical guidelines. This study aims to retrospectively review our preliminary experience and results of performing simultaneous thoracoscopic resection of coexisting diseases of the lung and thymus. METHODS: Simultaneous thoracoscopic resection was performed to remove coexisting thymic and pulmonary lesions in nine patients from August 2008 to November 2013. Patient demographics, preoperative assessment, surgical procedures and postoperative course of these patients were reviewed. RESULTS: There were four female and five male patients between 43 and 70 years old (median age, 64 years). Each patient had thymic neoplasm and solitary pulmonary lesion on chest computed tomography (CT) scan. Four patients underwent thoracoscopic lobectomy and thymectomy. One patient had thoracoscopic bronchovascular sleeve lobectomy combined with thymic cyst resection (TCR). The other four patients received pulmonary wedge resection and thymectomy (n=3)/TCR (n=1). The operation lasted from 35-480 min (median, 110 min). Intra-operative blood loss was 20-380 mL (median, 120 mL). Two patients developed post-operative pneumonia without mortality. All the patients were discharged home within 9 days after surgery. Two patients died from metastatic lung cancer 14 months after surgery. CONCLUSIONS: Simultaneous thoracoscopic resection of coexisting pulmonary and thymic lesions is safe and feasible in selected patients.

Surgical treatment of primary mediastinal myelolipoma.

OBJECTIVES: Primary mediastinal myelolipoma (PMM) is a rare benign tumour composed of haematopoietic tissue and mature adipose tissue. Here, we report the largest series aiming to investigate the outcomes of surgical treatment for patients with PMM. METHODS: We retrospectively reviewed the data of 12 patients operated in a single institute during the period between April 2008 and December 2014. RESULTS: There were 7 female and 5 male patients between 54 and 73 years old (median age, 64 years). Among them, 11 patients underwent unilateral (n = 10) or bilateral (n = 1) mass resection via video-assisted thoracic surgery (VATS), and 1 patient underwent a planned open thoracotomy due to a large tumour volume. The VATS operating time ranged from 20 to 65 min (median, 30 min) and intraoperative blood loss ranged from 20 to 60 ml (median, 30 ml). The open thoracotomy operating time was 120 min, and the blood loss was 1000 ml; thus, the patient received blood transfusion (2 units of RBCs). No operative mortalities or major postoperative complications were observed. All patients experienced a regular follow-up ranging from 2 to 80 months with a median follow-up of 18 months. No recurrence was observed at the time of evaluation. CONCLUSIONS: Surgical treatment is recommended for the diagnosis and treatment of PMM, while VATS is a safe and feasible option in most cases.

Non-grasping en bloc mediastinal lymph node dissection for video-assisted thoracoscopic lung cancer surgery.

BACKGROUND: This study aims to introduce an optimized method named "non-grasping en bloc mediastinal lymph node dissection (MLND)" through video-assisted thoracoscopic surgery (VATS). METHODS: Between February 2009 and July 2013, 402 patients with clinical stage I non-small cell lung cancer (NSCLC) underwent "non-grasping en bloc MLND" conducted by one surgical team. Target lymph nodes (LNs) were exposed following non-grasping strategy with simple combination of a metal endoscopic suction and an electrocoagulation hook or an ultrasound scalpel. In addition, dissection was performed following a stylized three-dimensional process according to the anatomic features of each station. Clinical and pathological data were prospectively collected and retrospectively reviewed. RESULTS: The postoperative morbidity and mortality were 17.4% (70/402) and 0.5% (2/402), respectively. The total number of LNs (N1 + N2) was 16.0 ± 5.9 (range of 5-52), while the number of N2 LNs was 9.5 ± 4.0 (range of 3-23). The incidences of postoperative upstaging from N0 to N1 and N2 disease were 7.7% and 12.2%, respectively. CONCLUSIONS: Non-grasping en bloc MLND enables en bloc dissection of mediastinal LNs with comparable morbidity and oncological efficacy while saving troubles of excessive interference of instruments and potential damage to the target LN.

Prognostic role of circulating tumor cells and disseminated tumor cells in patients with prostate cancer: a systematic review and meta-analysis.

Circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) displayed their roles in prognosis prediction in prostate cancer. The objective of the present study was to conduct a systematic review and meta-analysis of published literature while investigating the correlation between survival outcome and CTCs or DTCs counts in patients with prostate cancer. Relevant literature was searched in Pubmed and Embase. Survival data of included study were extracted. Forrest plots were used to estimate the effect of CTCs/DTCs on the survival of patients. Publication bias was evaluated using Begg's test. The estimated HRs and 95 % confidence interval for the effect of CTCs/DTCs on overall survival (OS) and biochemical relapse-free survival (bRFS) or disease-free survival (DFS) were 2.43 [2.07, 2.86] (p<0.00001) and 2.15 [1.69, 2.73] (p<0.00001), respectively. Subgroup analysis revealed that CTCs were also relevant to poor prognosis (hazard ratio (HR) 2.43 [2.05, 2.89] for OS, HR 2.46 [2.08, 2.90] for bRFS/DFS). A similar result was yielded in DTCs (1.47 [1.21, 1.80] for DFS). CTCs/DTCs could also predict poor OS in metastatic prostate cancer (2.37 [1.99, 2.82], p<0.00001) and in localized stage (HR 1.84 [1.47, 2.28], p<0.00001). In addition, CTCs/DTCs detected by different methods, especially by CellSearch system (HR for OS 2.36 [1.95, 2.85] and HR for bRFS/DFS 2.53 [1.66, 3.85]), were relevant to poor prognosis. Available evidence supported the notion of the strong prognostic value of CTCs. CTCs are promising biomarkers that are clinically implemented in the therapeutic decision-making process in patients with prostate cancer.

Video-assisted thoracic surgery for pulmonary sequestration compared with posterolateral thoracotomy.

OBJECTIVES: Pulmonary sequestration is a rare congenital malformation of the lungs. This study aims to evaluate the effectiveness of video-assisted thoracic surgery for the treatment of pulmonary sequestration in a larger series compared with posterolateral thoracotomy. METHODS: The files of 42 patients with pulmonary sequestration treated via video-assisted thoracic surgery (18 cases) and posterolateral thoracotomy (24 cases) between September 2005 and May 2012 from a single institute were retrospectively reviewed. Data were collected regarding the patient demographics, medical history, preoperative investigations, intraoperative findings, and postoperative course. RESULTS: All sequestration lung lesions were found in the lower lobes (31 on the left, 11 on the right), with feeding arteries arising from the thoracic aorta (34 cases) and the abdominal aorta (8 cases). Thirty-nine cases of sequestration were intralobar, and only 3 cases were extralobar. All patients achieved successful resection (including 37 lobectomies, 2 pneumonectomies, and 3 resections of the extralobar lesion). In the video-assisted thoracic surgery group, 1 case was converted to thoracotomy because of an injury to the aberrant artery; 1 case had injury to the left lower pulmonary vein and 1 case had injury to the aberrant artery, which were successfully treated without conversion. No significant differences were found between the 2 groups (video-assisted thoracic surgery vs posterolateral thoracotomy) in terms of the duration of operation, blood loss, amount of chest drainage, duration of chest drainage, length of postoperative hospital stay, and complications. CONCLUSIONS: Video-assisted thoracic surgery resection for pulmonary sequestration is feasible, although it should be performed by an experienced surgeon with awareness of the potential risk of severe vascular injury.

Prognostic value of vascular endothelial growth factor expression in resected gastric cancer.

BACKGROUND AND AIMS: Vascular endothelial growth factor (VEGF) is a potential prognostic biomarker for patients with resected gastric cancer. However, its role remains controversial. The objective of this study was to conduct a systematic review and meta-analysis of published literature. METHODS: Relevant literature was identified using Medline and survival data from published studies were collected following a methodological assessment. Quality assessment of eligible studies and meta-analysis of hazard ratio (HR) were performed to review the correlation of VEGF overexpression with survival and recurrence in patients with gastric cancer. RESULTS: Our meta-analysis included 44 published studies with 4,794 resected patients. VEGF subtype for the prediction of overall survival (OS) included tissue VEGF (HR=2.13, 95% CI 1.71-2.65), circulating VEGF (HR=4.22, 95% CI 2.47-7.18), tissue VEGF-C (HR=2.21, 95% CI 1.58-3.09), tissue VEGF-D (HR=1.73, 95% CI 1.25-2.40). Subgroup analysis showed that HRs of tissue VEGF for OS were, 1.78 (95% CI 0.90-3.51) and 2.31 (95% CI 1.82-2.93) in non-Asians and Asians, respectively. The meta-analysis was also conducted for disease free survival (DFS) and disease specific survival (DSS). CONCLUSION: Positive expression of tissue VEGF, circulating VEGF, VEGF-C and VEGF-D were all associated with poor prognosis in resected gastric cancer. However, VEGF demonstrated no significant prognostic value for non-Asian populations. Circulating VEGF may be better than tissue VEGF in predicting prognosis.