Surgical Treatment of Osteosarcoma Induced Distant Pre-Metastatic Niche in Lung to Facilitate the Colonization of Circulating Tumor Cells.

Recently, the major challenge in treating osteosarcoma patients is the metastatic disease, most commonly in the lungs. However, the underlying mechanism of recurrence and metastasis of osteosarcoma after surgical resection of primary tumor remains unclear. This study aims to investigate whether the pulmonary metastases characteristic of osteosarcoma is associated with surgical treatment and whether surgery contributes to the formation of pre-metastatic niche in the distant lung tissue. In the current study, the authors observe the presence of circulating tumor cells in patients undergoing surgical resection of osteosarcoma which is correlated to tumor recurrence. The pulmonary infiltrations of neutrophils and Gr-1+ myeloid cells are characterized to form a pre-metastatic niche upon the exposure of circulating tumor cells after surgical resection. It is found that mitochondrial damage-associated molecular patterns released from surgical resection contribute to the formation of pre-metastatic niche in lung through IL-1ß secretion. This study reveals that surgical management for osteosarcoma, irrespective of the primary tumor, might promote the formation of postoperative pre-metastatic niche in lung which is with important implications for developing rational therapies during peri-operative period.

Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.

Tumor metabolism and tumor immunity are inextricably linked. Targeting the metabolism of tumors is a point worth studying in tumor immunotherapy. Recently, the influence of the metabolism of tumors and immune cells on the occurrence, proliferation, metastasis, and prognosis of tumors has attracted more attention. Tumor tissue forms a specific tumor microenvironment (TME). In addition to tumor cells, there are also immune cells, stromal cells, and other cells in TME. To adapt to the environment, tumor cells go through the metabolism reprogramming of various substances. The metabolism reprogramming of tumor cells may further affect the formation of the tumor microenvironment and the function of a variety of cells, especially immune cells, eventually promoting tumor development. Therefore, it is necessary to study the metabolism of tumor cells and its effects on immune cells to guide tumor immunotherapy. Inhibiting tumor metabolism may restore immune balance and promote the immune response in tumors. This article will describe glucose metabolism, lipid metabolism, amino acid metabolism, and immune cells in tumors. Besides, the impact of metabolism on the immune cells in TME is also discussed for analyzing and exploring tumor immunotherapy.

Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer.

Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth.

Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy.

T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment.

Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.

Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin.

BACKGROUND: Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. METHODS: Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, ß-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. RESULTS: The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients' prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-ß. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8+ T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. CONCLUSIONS: Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.

Patient-Derived Tumor Xenografts Plus Ex Vivo Models Enable Drug Validation for Tenosynovial Giant Cell Tumors.

INTRODUCTION: Tenosynovial giant cell tumor (TGCT) is a locally aggressive tumor with colony-stimulating factor 1 receptor (CSF1R) signal expression. However, there is a lack of better in vivo and ex vivo models for TGCT. This study aims to establish a favorable preclinical translational platform, which would enable the validation of efficient and personalized therapeutic candidates for TGCT. PATIENTS AND METHODS: Histological analyses were performed for the included patients. Fresh TGCT tumors were collected and sliced into 1.0-3.0 mm3 sections using a sterilized razor blade. The tumor grafts were surgically implanted into subrenal capsules of athymic mice to establish patient-derived tumor xenograft (PDTX) mouse models. Histological and response patterns to CSF1R inhibitors evaluations were analyzed. In addition, ex vivo cultures of patient-derived explants (PDEs) with endpoint analysis were used to validate TGCT graft response patterns to CSF1R inhibitors. RESULTS: The TGCT tumor grafts that were implanted into athymic mice subrenal capsules maintained their original morphological and histological features. The "take" rate of this model was 95% (19/20). Administration of CSF1R inhibitors (PLX3397, and a novel candidate, WXFL11420306) to TGCT-PDTX mice was shown to reduce tumor size while inducing intratumoral apoptosis. In addition, the CSF1R inhibitors suppressed circulating nonspecific monocyte levels and CD163-positive cells within tumors. These response patterns of engrafts to PDTX were validated by ex vivo PDE cultures. CONCLUSIONS: Subrenal capsule supports the growth of TGCT tumor grafts, maintaining their original morphology and histology. This TGCT-PDTX model plus ex vivo explant cultures is a potential preclinical translational platform for locally aggressive tumors, such as TGCT.