Local and systemic inflammation triggers different outcomes of tumor growth related to infiltration of anti-tumor or pro-tumor macrophages

Background:Previous evidence suggests inflammation may be a double-edged sword with cancer-promoting and cancer suppressing function. In this study, we explore the impact of local and systemic inflammation on cancer growth.Methods:Female BALB/C mice were subcutaneously implanted with foreign body (plastic plates) to build up a local inflammation and intraperitoneally injected with PolyIC or lipopolysaccharides (LPS) to build up a systemic inflammation, followed by subcutaneous injection of 5 × 10⁵ colon cancer cells. Immunohistochemistry and enzyme linked immunosorbent assay were utilized to detect the Ki67 and interleukin (IL) 6, IL-1β, and monocyte chemoattractant protein-1 expression in the tumor tissues and serum, respectively. The distributions of immune cells and expression of toll-like receptors (TLRs) were evaluated by flow cytometry (FCM) and quantitative real time-polymerase chain reaction.Results:The results showed that local inflammation induced by foreign body implantation suppressed tumor growth with decreased tumor weight (P = 0.001), volume (P = 0.004) and Ki67 index (P < 0.001). Compared with the control group, myeloid-derived suppressive cells sharply decreased (P = 0.040), while CD4⁺ T cells slightly increased in the tumor tissues of the group of foreign body-induced local inflammation (P = 0.035). Moreover, the number of M1 macrophages (P = 0.040) and expression of TLRs, especially TLR3 (P < 0.001) and TLR4 (P < 0.001), were significantly up-regulated in the foreign body group. Contrarily, tumor growth was significantly promoted in LPS or PolyIC-induced systemic inflammation (P = 0.009 and 0.006). FCM results showed M1 type macrophages (P = 0.017 and 0.006) and CD8⁺ T cells (P = 0.031 and 0.023) were decreased, while M2 type macrophages (P = 0.002 and 0.007) were significantly increased in tumor microenvironment of LPS or PolyIC-induced systemic inflammation group. In addition, the decreased expression of TLRs was detected in LPS or PolyIC group.Conclusions:The foreign body-induced local inflammation inhibited tumor growth, while LPS or PolyIC- induced systemic inflammation promoted tumor growth. The results suggested that the different outcomes of tumor growth might be attributed to the infiltration of anti-tumor or pro-tumor immune cells, especially M1 or M2 type macrophages into tumor microenvironment.     

Lipidomic Profiling of Bronchoalveolar Lavage Fluid Extracellular Vesicles Indicates Their Involvement in Lipopolysaccharide-Induced Acute Lung Injury

Emerging data support the pivotal role of extracellular vesicles (EVs) in normal cellular physiology and disease conditions. However, despite their abundance, there is much less information about the lipid mediators carried in EVs, especially in the context of acute lung injury (ALI). Our data demonstrate that C57BL/6 mice subjected to intranasal Escherichia coli lipopolysaccharide (LPS)-induced ALI release, a higher number of EVs into the alveolar space, compared to saline-treated controls. EVs released during ALI originated from alveolar epithelial cells, macrophages, and neutrophils and carry a diverse array of lipid mediators derived from ω-3 and ω-6 polyunsaturated fatty acids (PUFA). The eicosanoids in EVs correlated with cellular levels of arachidonic acid, expression of cytosolic phospholipase A2, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome epoxygenase p450 proteins in pulmonary macrophages. Furthermore, EVs from LPS-toll-like receptor 4 knockout (TLR4^-/-) mice contained significantly lower amounts of COX and LOX catalyzed eicosanoids and ω-3 PUFA metabolites. More importantly, EVs from LPS-treated wild-type mice increased TNF-α release by macrophages and reduced alveolar epithelial monolayer barrier integrity compared to EVs from LPS-treated TLR4^−/− mice. In summary, our study demonstrates for the first time that the EV carried PUFA metabolite profile in part depends on the inflammatory status of the lung macrophages and modulates pulmonary macrophage and alveolar epithelial cell function during LPS-induced ALI.     

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE‐1 (phase 2) Japanese cohort

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), patients received a single cilta‐cel infusion at a target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10⁻⁵ threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.     

Association between squamous cell carcinoma antigen level and EGFR mutation status in Chinese lung adenocarcinoma patients

BackgroundTo investigate the association between squamous cell carcinoma antigen (SCCAg) level and epidermal growth factor receptor (EGFR) mutation status in Chinese lung adenocarcinoma patients.MethodsWe retrospectively analyzed 293 patients with lung adenocarcinoma, divided into EGFR mutant group (n = 178) and EGFR wild‐type group (n = 115). The general data and laboratory parameters of the two groups were compared. We used univariable and multivariable logistic regression to analyze the association between SCCAg level and EGFR mutation. Generalized additive model was used for curve fitting, and a hierarchical binary logistic regression model was used for interaction analysis.ResultsSquamous cell carcinoma antigen level in the EGFR wild‐type group was significantly higher than that in the mutant group (p < 0.001). After adjusting for confounding factors, we found that elevated SCCAg was associated with a lower probability of EGFR mutation, with an OR of 0.717 (95% CI: 0.543–0.947, p = 0.019). For the tripartite SCCAg groups, the increasing trend of SCCAg was significantly associated with the decreasing probability of EGFR mutation (p for trend = 0.015), especially for Tertile 3 versus Tertile 1 (OR = 0.505; 95% CI: 0.258–0.986; p = 0.045). Curve fitting showed that there was an approximate linear negative relationship between continuous SCCAg and EGFR mutation probability (p = 0.020), which was first flattened and then decreased (p < 0.001). The association between the two was consistent among different subgroups, suggesting no interaction (all p > 0.05).ConclusionThere is a negative association between SCCAg level and EGFR mutation probability in Chinese lung adenocarcinoma patients.     

Influence of response to prior docetaxel on sensitivity to cabazitaxel in prostate cancer patients with PTEN alterations

The purpose of this study was to investigate factors predicting the sensitivity to cabazitaxel therapy in metastatic castration‐resistant prostate cancer (mCRPC) patients with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) alterations. This single‐institution, retrospective study included 12 mCRPC patients with PTEN alterations who had received cabazitaxel therapy. Five patients (41%) responded to cabazitaxel therapy with a prostate‐specific antigen (PSA) level decline of ≥30% from baseline, and all of them had responded to prior docetaxel therapy with a PSA decline of ≥30%. None of the patients with a poor response to prior docetaxel therapy responded well to cabazitaxel therapy. Of the seven patients who did not respond to cabazitaxel and whose PSA declined from baseline was <30%, five (71%) were also refractory to prior docetaxel therapy. The PSA responses to docetaxel and cabazitaxel were significantly correlated (p = 0.027). Kaplan–Meier analysis revealed that progression‐free survival (PFS) for cabazitaxel was significantly shorter for prior docetaxel nonresponders (3.3 versus 9.1 months, p = 0.028). Multivariate analysis revealed that a poor response to prior docetaxel (PSA decline < 30%) (hazard ratio [HR] = 6.382, 95% confidence interval [CI] 1.172–34.750, p = 0.032) and baseline PSA of ≥20 ng/ml (HR = 33.584, 95% CI 2.332–483.671, p = 0.010) were independent prognostic factors for PFS with cabazitaxel therapy. These results demonstrate cross‐resistance between docetaxel and cabazitaxel. The response to prior docetaxel therapy can influence the sensitivity to cabazitaxel therapy in mCRPC patients with PTEN alterations.     

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.     

Adenovirus-IL-10 relieves chronic rejection after mouse heart transplantation by inhibiting miR-155 and activating SOCS5

Objective: Chronic rejection remains the main factor that influence long-term survival of patients after heart transplantation. Interleukin-10 (IL-10) play critical role in macrophages-mediated transplant immune responses. We investigated the mechanism of IL-10 in macrophage related chronic rejection after mouse heart transplantation.Methods: Mouse heart transplant chronic rejection model was established to evaluate pathological changes in the allograft. Myocardial interstitial fibrosis, apoptosis, and inflammatory factor levels were detected in ad-IL-10-treated mice. The positive iNOS⁺ and Arg-1⁺ expressions, macrophage subset changes, and the proportion of regulatory T-cells (Tregs) and TIGIT⁺ Tregs were quantified by flow. In in vitro experiments, ad-IL-10 was transfected into macrophages followed by detection of apoptosis, phagocytosis, and CD163, CD16/32, and CD206 expression. The expression and relationships between IL-10, miR-155, and SOCS5 were also detected and verified. A rescue experiment was performed to evaluate macrophage function through the combined treatment of ad-IL-10 and overexpression of miR-155.Results: Significantly decreased IL-10 expression in chronic rejection during mouse heart transplantation was observed. Ad-IL-10-treated mice showed decreased pathological injury, perivascular fibrosis, apoptosis, inflammation, and iNOS⁺ and CD16/32⁺ expression, and increased Treg/TIGIT⁺ Treg cell, Arg-1⁺ and CD206⁺ cell proportion. Ad-IL-10-treated macrophages in vitro showed reduced apoptosis, improved phagocytosis, and M2 polarization. Mechanically, IL-10 negatively regulated miR-155 to activate SOCS5. Overexpression of miR-155 reversed IL-10 mediated-positive regulation of macrophage function.Conclusion: IL-10 downregulated miR-155 and activated SOCS5, thereby promoting macrophage M2 polarization to relieve chronic rejection after heart transplantation.     

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12264-022-00910-0.     

Polatuzumab Vedotin联合利妥昔单抗和苯达莫司汀治疗复发/难治性弥漫大B细胞淋巴瘤的单中心疗效和安全性分析

  目的  探讨真实世界大B细胞淋巴瘤（large B-cell lymphoma,LBCL）嵌合抗原受体-T（chimeric antigen receptor-T,CAR-T）细胞治疗失败后的结局。   方法  回顾性分析2018年7月至2022年12月于南昌大学第一附属医院接受CD19 CAR-T细胞治疗后出现疾病复发/难治性16例LBCL患者的临床资料,分析其后续治疗和预后。  结果  16例患者中男性10例、女性6例,中位年龄53.5（16～72）岁,其预后极差,中位总生存期（median overall survival,mOS）仅为5.7个月（95%CI：5.1～6.3）。积极后续抗肿瘤治疗患者12例（75%）,mOS为9.8个月（95%CI：3.3～16.3）;姑息治疗4例（25%）,mOS仅为2.1个月（95%CI：0～4.8）,差异具有统计学意义（P<0.05）。后续抗肿瘤方案包括Pola-BR为4例（33.3%）、BTK抑制剂4例（33.3%）、抗PD-1抗体2例（16.7%）和免疫化疗2例（16.7%）,最佳疗效为部分缓解4例（33.3%）。BTK抑制剂组2例（50%）为部分缓解,mOS为10.8个月（95%CI：3.4～18.1）,较其他方案似有获益趋势,但差异无统计学意义（P>0.05）。  结论  CAR-T治疗后复发或进展的LBCL患者预后差,治疗手段局限,如何合理化分层使用后线治疗策略未来值得探索。     

CAR-T在甲状腺癌免疫治疗中的研究进展

大多数甲状腺癌患者进行以外科治疗为主的综合治疗可以取得良好的预后,但目前晚期甲状腺癌治疗手段匮乏。采用体外基因编辑技术的嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）免疫疗法在血液系统肿瘤中得到应用并取得了良好的治疗效果。以此为基础,CAR-T开始在实体肿瘤中尝试使用,但效果欠佳。CAR-T在晚期甲状腺癌中的研究已有开展,目前仍局限在临床前的基础研究,相关临床试验较少且缺乏试验结果报道。本文将相关报道进行综述,旨在为今后的研究提供参考。