Landscape of Immune Checkpoint Inhibition in Carcinosarcoma (MMMT): Analysis of IDO-1, PD-L1 and PD-1.
癌肉瘤 (MMMT) 免疫检查点抑制的景观: IDO-1 、 PD-L1 和 PD-1 分析。
- 作者列表："Hacking S","Chavarria H","Jin C","Perry A","Nasim M
BACKGROUND:Carcinosarcoma (CS) or malignant mixed Müllerian tumor (MMMT), is a rare malignant biphasic tumor, which contains both a malignant epithelial and mesenchymal component. That being said, they have an aggressive clinical course. Given that immune checkpoint inhibitors have mustered significant excitement in the oncology world - immunotherapy could offer significant promise to this poor prognostic cancer subtype. A total of 75 carcinosarcoma cases were identified in our institutional database from 2010 to 2019 and immunohistochemistry for PD-L1, PD-1 and IDO-1 was performed. Out of the 75 patients, 65(87 %) demonstrated >1 % PD-1 expression and 50(67 %) expressed >1 % PD-L1 in either the tumoral and immune stromal components. 29 (39 %) cases demonstrated >20 % PD-1 expression and 14 (19 %) cases expressed >20 % PD-L1. 41(55 %) cases demonstrating co-expression of PD-1 and PD-L1. For IDO-1 64 (85 %) patients showed at least >5 %, while 34 (45 %) showed staining above 20 %. 45 patients (60 %) showed co-expression of IDO-1 and PD-L1, while 59 (79 %) patients had co-expression of IDO and PD-1 above 5 and 1 % respectively. Regarding clinicopathologcial features; older patients (> 65) were more likely to express PD-L1 (>1 %) and IDO-1 (>20 %). For tumor size, IDO-1 expression (>5 %), along with PD-1/IDO-1 Co-expression (>1/5 %), was associated with larger tumor size (>5cm). For myometrial invasion, CSs with >50 % invasion were more likely to express IDO-1 (>20 %) and PD-1/IDO-1 (>1/5 %). Ultimately, the effect of IDO-1, PD-1 and PD-L1 on the clinical profile may be less important than its potential use as a immunotherapeutic, where safe and effective corresponding drugs could be used to treat particular patient populations. Future clinical trials are needed to decipher the association between immune check point inhibitor expression and therapeutic response. This is the only way to definitively prove immune checkpoint immunohistochemistry as predictive biomarkers in this cancer subtype.
背景: 癌肉瘤 (CS) 或恶性混合性苗勒管肿瘤 (MMMT) 是一种罕见的恶性双相肿瘤，同时含有恶性上皮和间质成分。也就是说，他们有一个积极的临床过程。鉴于免疫检查点抑制剂在肿瘤学世界中引起了显著的兴奋 -- 免疫治疗可以为这种预后不良的癌症亚型提供显著的希望。我们的机构数据库中 2010 年至 2019 年共确定了 75 例癌肉瘤病例，并进行了 PD-L1 、 PD-1 和 IDO-1 的免疫组化。75 例患者中，65 例 (87%) 在肿瘤和免疫基质成分中表达> 1% PD-1，50 例 (67%) 表达> 1% PD-L1。29 例 (39%) PD-1 表达> 20%，14 例 (19%) PD-L1 表达> 20%。41 例 (55%) 显示 PD-1 与 PD-L1 共表达。对于 IDO-1，64 例 (85%) 患者显示至少> 5%，而 34 例 (45%) 显示染色在 20% 以上。45 例 (60%) 患者显示 IDO-1 和 PD-L1 共表达，59 例 (79%) 患者 IDO 和 PD-1 共表达分别在 5 和 1% 以上。关于临床病理特征; 老年患者 (> 65) 更可能表达 PD-L1 (>1%) 和 IDO-1 (>20%)。对于肿瘤大小，IDO-1 表达 (>5 ))，以及 PD-1/IDO-1 共表达 (>1/5 )) 与肿瘤大小 (> 5厘米) 相关。对于肌层浸润，浸润> 50% 的 CSs 更可能表达 IDO-1 (>20%) 和 PD-1/IDO-1 (>1/5)。最终，IDO-1，PD-1 和 PD-L1 对临床特征的影响可能不如其作为免疫治疗的潜在用途重要,安全有效的相应药物可用于治疗特定患者人群。需要未来的临床试验来破译免疫检查点抑制剂表达与治疗反应之间的关联。这是明确证明免疫检查点免疫组化作为该癌症亚型预测生物标志物的唯一方法。
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.