Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in the dendritic cell-based vaccine.

Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2 , and transforming growth factor-β. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8(+) T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8(+) T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy.雑誌掲載時のタイトル: Cancer-associated　fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine滋賀医科大学平成26年

Evaluation of predictive factors related to the presence or absence of supplemental oxygen therapy and comparison of physical functions after video-assisted thoracic surgery.

　We performed a retrospective study of 102 individuals to evaluate predictive factors for needing supplemental oxygen therapy following video-assisted thoracic surgery (VATS) and to compare patients’ physical functions before and after surgery. Prior to surgery, we evaluated quadriceps torque, 6-minute walk distance (6MWD), timed up and go test, and grip strength. During the 6MWD, patients’ oxygen saturation was recorded every minute. Quadriceps torque and 6MWD were evaluated again following surgery. The indication for supplemental oxygen therapy was determined based on desaturation (<85%) during the 6MWD in room air. A total of 14 patients needed oxygen therapy at discharge (group A), while 88 patients did not need oxygen therapy (group B). In group A, the postoperative 6MWD was repeated with supplemental oxygen. Compared with the same parameters in group B, in group A the percentage diffusing capacity for carbon monoxide was significantly lower (p=0.011), while a history of smoking (p=0.016), exercise-induced hypoxemia (EIH, p<0.001), chronic obstructive pulmonary disease (p<0.001), and interstitial pneumonia (p=0.008) were significantly higher. Logistic regression analysis showed that EIH was an independent risk factor for requiring supplemental oxygen therapy following surgery (odds ratio: 46.2, 95% CI: 9–237.1; p<0.001). In group A, patients’ minimum oxygen saturation was significantly improved by oxygen administration (83.4±3.4 vs. 87.7±3.3, p=0.002), but there was no difference in walking distance (359.5±64.2 vs. 353.6±41.6, p=0.482). Our data indicate that patients should be preoperatively evaluated to predict postoperative hypoxemia and that this evaluation could complement the prediction of postoperative need for oxygen therapy

Perioperative changes in respiratory impedance in lobectomy and their clinical impact.

Background:Respiratory function declines after lung resection. However, perioperative changes in respiratory impedance and their clinical significance are unclear. The forced oscillation technique can measure respiratory impedance during quiet breathing and possibly early after surgery. We investigated respiratory impedance changes before and after lung lobectomy and examined the correlation of impedance with clinical factors.Methods:We prospectively included patients who underwent lobectomy between February 2018 and March 2020 and measured respiratory impedance by forced oscillation preoperatively and postoperative days 1 and 7. We statistically analyzed changes in perioperative forced oscillation measurements and their correlation with clinical factors, including subjective symptoms. The modified British Medical Research Council scale and the chronic obstructive pulmonary disease (COPD) assessment test were used for scoring subjective symptoms.Results:Forty-four subjects were included, in whom respiratory impedance could be measured from postoperative day 1. The respective mean values for forced oscillation measurements preoperatively and at postoperative days 1 and 7 were as follows: respiratory resistance, 5 Hz: 2.28, 2.77, and 2.75; respiratory resistance, 20 Hz: 2.00, 2.36, and 2.32; difference in respiratory resistance at 5 and 20 Hz: 0.28, 0.40, and 0.43; respiratory reactance, 5 Hz: -0.31, -0.65, and -0.56; resonant frequency: 7.45, 10.41, and 9.81; and low-frequency reactance area: 1.33, 3.27, and 2.84. These changes were statistically significant (P<0.01). Besides the difference in respiratory resistance at 5 and 20 Hz, all other measurements on postoperative day 7 were relatively weakly correlated with the modified Medical Research Council scale score at this time point (all P<0.05). Respiratory complications correlated with the respiratory resistance difference, respiratory reactance, and resonant frequency on day 7 (R =0.415, -0.421, and 0.441), while the latter also correlated with postoperative hypoxemia on day 1 (R =0.433).Conclusions:Respiratory impedance was measurable even early after surgery and significantly changed postoperatively. As the sample size was small and appeared to be biased, assessing respiratory impedance and clinical factors in detail was difficult. Since respiratory impedance is suggested to be associated with clinical factors that affect the postoperative course, it is necessary to accumulate cases and observe them over longer periods

Does sarcopenia affect postoperative short- and long-term outcomes in patients with lung cancer?-a systematic review and meta-analysis.

Background:Lung cancer patients frequently suffer from sarcopenia, and reports on the association of resectable lung cancer and their postoperative outcomes are increasing. Information on whether sarcopenia has any impact on short- and long-term postoperative outcomes in patients surgically treated for non-small cell lung cancer remains insufficient. Furthermore, reports vary regarding the pathological stage, surgical procedure, diagnostic tool of sarcopenia, cut-off value, prognosis, and postoperative complications. We believe that sarcopenia assessment should be included as one of the factors which affect the surgical outcomes of lung cancer. Thus, we conducted a review and meta-analysis to ascertain the association between sarcopenia and postoperative outcomes.Methods:We performed a systematic literature search in PubMed/MEDLINE. Studies included cases defined sarcopenia, received lung cancer surgery, assessed postoperative complications, and prognosis. The pooled odds ratios for survival and postoperative complications, with 95% confidence intervals, were generated using Review manager 5.3.Results:A total of ten retrospective studies were eligible for this meta-analysis, including a total of 2,643 non-small cell lung cancer patients. All reviews used skeletal muscle mass as a diagnostic tool for sarcopenia. Sarcopenia was associated with worse survival outcomes and increased postoperative complications in patients with resected lung cancer.Conclusions:Sarcopenia is an independent risk factor for postoperative death and postoperative complications in patients who have undergone surgery. It is necessary to explore the mechanism of sarcopenia and optimal intervention, such as exercise, nutrition, or drug therapy

Survival and prognostic factors in patients undergoing extended pulmonary metastasectomy.

Extended pulmonary metastasectomy has become feasible in patients with extrapulmonary metastases and multiple or bilateral pulmonary metastases. Even peritoneal dissemination is considered to be curable in modern medicine. Therefore, it is necessary to analyze the prognosis of patients undergoing complete pulmonary metastasectomy. A total of 80 patients who underwent pulmonary resection for lung metastases were retrospectively analyzed. The eligibility criteria for the present study were as follows: i) the primary tumor was controlled; ii) if extrapulmonary metastases (including peritoneal dissemination) existed, these were controlled by local treatment or such treatment was planned; iii) the one to three months follow-up computed tomography (CT) following the first assessment revealed no increase of pulmonary metastatic disease; iv) pulmonary metastases could be resected completely. The overall 5- and 10-year survival rates were 71.7 and 41.5%, respectively. Applying the extended criteria for surgery, the present study demonstrated that pulmonary metastasectomy resulted in a good patient prognosis

Sarcopenia increases the risk of post-operative recurrence in patients with non-small cell lung cancer.

Background:Sarcopenia is among the most prevalent and serious cancer-related symptom, and is strongly correlated with a poor prognosis. Moreover, it reportedly predicts poor prognosis after surgery in patients with lung cancer. However, it is unclear whether sarcopenia directly affects post-operative recurrence. The purpose of this study was to evaluate whether sarcopenia can be a risk indicator for post-operative recurrence, and whether it suppresses anti-tumor immunity, in a cohort of patients with resected non-small cell lung cancer.Methods:This study retrospectively reviewed the data of 256 consecutive patients who underwent curative lobectomy and lymph node dissection for non-small cell lung cancer at our institution. The psoas muscle mass index was calculated as the total psoas muscle area at the third lumbar vertebral level/height2 (cm2/m2). Sarcopenia was defined by a psoas muscle mass index of under 5.03 cm2/m2 and 3.17 cm2/m2 in male and female patients, respectively. Post-operative prognosis and cumulative incidence of recurrence rates were calculated.Results:The 5-year overall survival and disease-free survival rates post-surgery were 59.5% and 38.6%, respectively, in patients with sarcopenia versus 81.1% and 72.1%, respectively, in patients without sarcopenia (p < 0.001). The 5-year cumulative incidence of recurrence rate in patients with sarcopenia was significantly higher than those without sarcopenia (49.9% versus 22.4%, respectively) in every pathological stage. Pathological stages II and III (hazard ratio, 3.36; p = 0.004), histological type (hazard ratio, 2.31; p = 0.025), and sarcopenia (hazard ratio, 2.52; p = 0.001) were independent risk factors for post-operative recurrence according to multivariate analysis.Conclusion:Sarcopenia is a risk indicator for post-operative recurrence in patients with non-small cell lung cancer

Locoregional recurrence via mucus-mediated extension following lung resection for mucinous tumors.

Background:Clinically, locoregional recurrences following mucinous tumor resection are often experienced. However, it remains unclear whether mucinous tumors directly affect local recurrence or not, and if so, the mechanism is not known. Therefore, we investigated whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and whether mucus extension is a risk factor for locoregional recurrence.Methods:The data of 152 patients who underwent pulmonary resection for metastases were reviewed. When mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. In mucinous tumors, when mucus was identified within the air spaces in the normal lung parenchyma, beyond the edge of the tumor, we assigned the tumor as positive for "mucus extension."Results:The 5-year cumulative incidence of locoregional recurrence in patients with mucinous tumors was 48.1%, which was significantly higher than that observed in those with non-mucinous tumors (14.9%). Within the mucinous tumor, the presence of mucus extension beyond the tumor edge was an independent risk factor for locoregional recurrence after pulmonary resection (hazard ratio, 5.52; P = 0.019).Conclusions:During the resection of mucinous cancer, surgeons should maintain sufficient distance from the tumor edge to prevent locoregional recurrences

Dynamic perfusion digital radiography for predicting pulmonary function after lung cancer resection.

Background:Accurate prediction of postoperative pulmonary function is important for ensuring the safety of patients undergoing radical resection for lung cancer. Dynamic perfusion digital radiography is an excellent and easy imaging method for detecting blood flow in the lung compared with the less-convenient conventional lung perfusion scintigraphy. As such, the present study aimed to confirm whether dynamic perfusion digital radiography can be evaluated in comparison with pulmonary perfusion scintigraphy in predicting early postoperative pulmonary function and complications.Methods:Dynamic perfusion digital radiography and spirometry were performed before and 1 and 3 months after radical resection for lung cancer. Correlation coefficients between blood flow ratios calculated using dynamic perfusion digital radiography and pulmonary perfusion scintigraphy were then confirmed in the same cases. In all patients who underwent dynamic perfusion digital radiography, the correlation predicted values calculated from the blood flow ratio, and measured values were examined. Furthermore, ppo%FEV1 or ppo%DLco values, which indicated the risk for perioperative complications, were examined.Results:A total of 52 participants who satisfied the inclusion criteria were analyzed. Blood flow ratios measured using pulmonary perfusion scintigraphy and dynamic perfusion digital radiography showed excellent correlation and acceptable predictive accuracy. Correlation coefficients between predicted FEV1 values obtained from dynamic perfusion digital radiography or pulmonary perfusion scintigraphy and actual measured values were similar. All patients who underwent dynamic perfusion digital radiography showed excellent correlation between predicted values and those measured using spirometry. A significant difference in ppo%DLco was observed for respiratory complications but not cardiovascular complications.Conclusions:Our study demonstrated that dynamic perfusion digital radiography can be a suitable alternative to pulmonary perfusion scintigraphy given its ability for predicting postoperative values and the risk for postoperative respiratory complications. Furthermore, it seemed to be an excellent modality because of its advantages, such as simplicity, low cost, and ease in obtaining in-depth respiratory functional information.Trial registration:Registered at UMIN on October 25, 2017. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000033957Registration number: UMIN00002971

Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin.

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model