Clinical recommendations on diagnosis and treatment of immune checkpoint inhibitor-induced renal immune-related adverse events.
- 作者列表："Zheng K","Qiu W","Wang H","Si X","Zhang X","Zhang L","Li X
:Immune checkpoint inhibitors (ICIs) are nowadays widely used in clinical oncology treatment, and significantly improve the prognosis of cancer patients. However, overactivation of T cells and related signaling pathways caused by ICIs can also induce immune-related adverse effects (irAEs). Renal immune side-effects are relatively rare, but some are serious and fatal. Acute kidney injury (AKI), diagnosed mainly by percentage increases in serum creatinine (sCr), is the most common clinical manifestation, while acute tubulointerstitial nephritis (ATIN) is the main cause of ICI-related AKI. Urinalysis analysis and sediment evaluation, 24 hour urine protein and sCr are helpful in screening and monitoring renal irAEs. Multiple potential causes for AKI are involved during cancer therapy, and should be differentiated from the immune mechanisms of ICIs. Under these circumstances, a renal biopsy should be considered which is essential for clinical decision-making. Steroids are an effective treatment option for renal irAEs. Most patients who experience ICI-related ATIN achieve a partial or complete renal recovery with prompt diagnosis and treatment. Multidisciplinary collaborations of different specialists will improve the effectiveness and outcome in the management of ICI irAEs.
免疫检查点抑制剂 (Immune checkpoint inhibitors，ICIs) 目前广泛应用于临床肿瘤治疗，显著改善肿瘤患者的预后。然而，ICIs 引起的 T 细胞和相关信号通路的过度激活也可诱导免疫相关不良反应 (irAEs)。肾免疫副作用相对少见，但有些是严重和致命的。急性肾损伤 (AKI) 是最常见的临床表现，主要通过血清肌酐 (sCr) 百分比升高来诊断，而急性肾小管间质性肾炎 (ATIN) 是 ICI 相关 AKI 的主要病因。尿液分析和沉渣评价、 24 小时尿蛋白定量和 sCr 有助于筛查和监测肾脏疾病。在癌症治疗过程中，AKI 的多种潜在病因参与其中，应与 ICIs 的免疫机制相鉴别。在这种情况下，应考虑肾活检，这对临床决策至关重要。类固醇是一种有效的治疗肾脏 irAEs 的选择。大多数经历 ICI 相关 ATIN 的患者在及时诊断和治疗的情况下达到部分或完全肾脏恢复。不同专家的多学科合作将提高 ICI irAEs 管理的有效性和结果。
METHODS::Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for Transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow derived macrophages (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the "first in class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
METHODS::Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.
METHODS::Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.