Tumor-associated Microenvironment Research Articles

Single-cell transcriptome-based multilayer network biomarker for predicting prognosis and therapeutic response of gliomas.

Occurrence and development of cancers are governed by complex networks of interacting intercellular and intracellular signals. The technology of single-cell RNA sequencing (scRNA-seq) provides an unprecedented opportunity for dissecting the interplay between the cancer cells and the associated microenvironment. Here we combined scRNA-seq data with clinical bulk gene expression data to develop a computational pipeline for identifying the prognostic and predictive signature that connects cancer cells and microenvironmental cells. The pipeline was applied to glioma scRNA-seq data and revealed a tumor-associated microglia/macrophage-mediated EGFR/ERBB2 feedback-crosstalk signaling module, which was defined as a multilayer network biomarker (MNB) to predict survival outcome and therapeutic response of glioma patients. We used publicly available clinical data sets from large cohorts of glioma patients to examine the prognostic significance and predictive accuracy of the MNB, which outperformed conventional gene biomarkers and other methods. Additionally, the MNB was found to be predictive of the sensitivity or resistance of glioma patients to molecularly targeted therapeutics. Moreover, the MNB was an independent and the strongest prognostic factor when adjusted for clinicopathologic risk factors and other existing gene signatures. The robustness of the MNB was further tested on additional data sets. Our study presents a promising scRNA-seq transcriptome-based multilayer network approach to elucidate the interactions between tumor cell and tumor-associated microenvironment and to identify prognostic and predictive signatures of cancer patients. The proposed MNB method may facilitate the design of more effective biomarkers for predicting prognosis and therapeutic resistance of cancer patients.

Tumor-associated inflammatory microenvironment in non-small cell lung cancer: correlation with FGFR1 and TLR4 expression via PI3K/Akt pathway.

The tumor-associated inflammatory microenvironment plays a pivotal role in human non-small cell lung cancer (NSCLC) development. FGFR1 and TLR4 involve in the regulation of inflammatory microenvironment of NSCLC.However, the relationship between the FGFR1 and TLR4 signaling and the mechanisms that involved in tumor-associated microenvironment are still unclear. We investigated the expression of FGFR1 and TLR4 in cancerous tissues and noncancerous lung tissues from 60 primary NSCLC patients using immunohistochemical staining. Three cell lines (A549, PC-9 and SK-MES-1) were used for in vitro studies. We demonstrated that the expression of FGFR1 and TLR4 was significantly correlated (r=0.504, p<0.05) in NSCLC tissues. We revealed that activation of FGFR1 and TLR4 pathways by specific signaling agonist increased Akt phosphorylation. Further results showed that FGFR1 and TLR4 regulated cell proliferation and migration and promoted the production of proinflammatory or immunosuppressive cytokines TNF-α and IL-6. Meanwhile, the PI3K inhibitor LY294002 rescued these changes. Taken together, our results indicate that the FGFR1 expression level is positively correlated with TLR4 expression level in human NSCLC tissues. The activation of FGFR1 and TLR4 in cancer cells contributes to inflammatory microenvironment via PI3K/Akt signaling and may make a significant contribution to the progression of human NSCLC.

Colorectal Cancer Is Associated with a Deficiency of Lipoxin A4, an Endogenous Anti-inflammatory Mediator.

Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to tumorigenesis. Among these mediators, lipoxin A4 (LXA4) has potent anti-carcinogenic properties, and may serve as key target for modulating inflammation-associated cancer like colorectal cancer. The purpose of present study was to clarify the roles of LXA4 in colorectal cancer. We investigated the effects and underlying mechanisms of LXA4 in colorectal cancer and its relationship with tumor-associated inflammation and immune microenvironment by employing clinical samples and mouse colorectal cancer cell line CT26-bearing tumor model as well as colorectal cancer cells. It was found that colorectal cancer is associated with dysregulation of immune microenvironment and deficiency of LXA4 that could play different roles at different stages of tumor growth: inhibiting early but promoting late tumor growth. Analysis of peripheral immune cells in subcutaneous xenograft mice model disclosed that early LXA4 treatment induced lymphocytes and inhibited neutrophils and monocytes, while late LXA4 treatment induced neutrophils but inhibited lymphocytes. Detailed analysis of tumor microenvironment revealed that early LXA4 treatment could inhibit inflammatory mediators expressions and leukocytes infiltration into tumor. Furthermore, LXA4 could suppress the expressions of p-ERK, p-P38 and NF-κB in subcutaneous xenograft. Additionally, LXA4 could inhibit the proliferation and migration of colorectal cancer cells, and, meanwhile, inhibit the proliferation and migration of colorectal cancer cells stimulated by activated macrophage-conditioned media. These findings suggest that colorectal cancer is associated with a deficiency of LXA4 that could suppress colorectal cancer via modulating tumor-associated inflammation and immune microenvironment as well as inhibiting colorectal cancer cell development.

CHARACTERISTICS OF BONE MARROW MICROENVIRONMENT IN MULTIPLE MYELOMA BEFORE AND AFTER TREATMENT

The purpose of the study is to evaluate the morphological and functional features of the tumor microenvironment and the cultural characteristics of mesenchymal stromal cells (MSC) of patients with multiple myeloma (MM) before and after treatment. Material and methods. Parenchymal and stromal bone marrow tissue in iliac bone trepanobiopsy of 32 patients with MM aged from 48 to 78 years (median age 56 years) before and after treatment was investigated. The study applied histological, immunohistochemical and cultural methods. Results and discussion. Сhanges of stromal microenvironment of bone marrow in all patients with MM have been revealed: increased microvascular density and the number of endosteal stromal cells, strengthening of reticulin fiber in subendosteal and perivascular spaces. Increased angiogenesis correlates with the number of plasma cells in the myelogram ( r = 0.58; p < 0.05) and with the type of bone marrow infiltration ( r = 0.85; р < 0.05), as well as with osteodestructive changes in the patient’s history ( r = 0.65; p < 0.05). Significant changes in MSC cultures, both before and after therapy, including autologous hematopoietic stem-cell transplantation, were shown. Bone marrow MSC of patients with MM had decreased speed of proliferation (2.4 times on average), total time of passaging from 7 to 5 passages, increased expression of markers associated with myofibroblastic phenotype and aging (smooth muscle actin, β-galactosidase) compared to healthy donors. Conclusion. MSC cultures and BM niche forming elements of patients with MM have signs of tumor-associated microenvironment, despite the treatment of the underlying disease.

Inflammation and Cancer: In Medio Stat Nano.

Cancer treatment still remains a challenge due to the several limitations of currently used chemotherapeutics, such as their poor pharmacokinetics, unfavorable chemical properties, as well as inability to discriminate between healthy and diseased tissue. Nanotechnology offered potent tools to overcome these limitations. Drug encapsulation within a delivery system permitted i) to protect the payload from enzymatic degradation/ inactivation in the blood stream, ii) to improve the physicochemical properties of poorly water-soluble drugs, like paclitaxel, and iii) to selectively deliver chemotherapeutics to the cancer lesions, thus reducing the off-target toxicity, and promoting the intracellular internalization. To accomplish this purpose, several strategies have been developed, based on biological and physical changes happening locally and systemically as a consequence of tumorigenesis. Here, we will discuss the role of inflammation in the different steps of tumor development and the strategies based on the use of nanoparticles that exploit the inflammatory pathways in order to selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes.

Antimyeloma Effect of the Simultaneous Inhibition of MCL-1 (with S63845) and BCL-2 (with Venetoclax) in the Presence of the Microenvironment

Antimyeloma Effect of the Simultaneous Inhibition of MCL-1 (with S63845) and BCL-2 (with Venetoclax) in the Presence of the Microenvironment

Biology of Tumor Associated Macrophages in Diffuse Large B Cell Lymphoma.

The tumor associated microenvironment is known to play a vital role during the development and progression of different malignant tumors. As a part of tumor microenvironment, tumor associated macrophages (TAMs) are crucial for the genesis, proliferation, metastasis, and survival of tumor cells. Recently, more and more studies showed that TAMs were related with poor clinical status and survival in patients with diffuse large B cell lymphoma (DLBCL). Considering the complex roles which TAMs play in the tumor microenvironment of DLBCL, the aim of this study was to review the biological mechanisms between TAMs and DLBCL cells, including extracellular matrix remodeling and angiogenesis promotion, tumor promotion, immune suppression, and phagocytosis inhibition. This review will help us to further understand the comprehensive impact of TAMs on DLBCL and explore possible prognostic markers and therapeutic targets.

USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and \u03b2-TrCP and promotes cancer malignancy

We have previously demonstrated that USP24 is involved in cancer progression. Here, we found that USP24 expression is upregulated in M2 macrophages and lung cancer cells. Conditioned medium from USP24-knockdown M2 macrophages decreases the migratory and chemotactic activity of lung cancer cells and the angiogenic properties of human microvascular endothelial cell 1 (HMEC-1). IL-6 expression is significantly decreased in USP24-knockdown M2 macrophages and lung cancer cells, and IL-6-replenished conditioned medium restores the migratory, chemotactic and angiogenetic properties of the cells. USP24 stabilizes p300 and β-TrCP to increase the levels of histone-3 acetylation and NF-κB, and decreases the levels of DNMT1 and IκB, thereby increasing IL-6 transcription in M2 macrophages and lung cancer cells, results in cancer malignancy finally. IL-6 has previously been a target for cancer drug development. Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.

"Smart" Nanoprobes for Visualization of Tumor Microenvironments.

Physiological parameters in tumor microenvironments, including hypoxia, low extracellular pH, enzymes, reducing conditions, and so on, are closely associated with the proliferation, angiogenesis, invasion, and metastasis of cancer, and impact the therapeutic administrations. Therefore, monitoring the tumor microenvironment is significant for diagnosing tumors, predicting the invasion potential, evaluating therapeutic efficacy, planning the treatment, and cancer prognostics. Noninvasive molecular imaging technologies combined with novel "smart" nanoparticle-based activatable probes provide a feasible approach to visualize tumor-associated microenvironment factors. This review summarizes recent achievements in the designs of "smart" molecular imaging nanoprobes responding to the tumor microenvironment-related features, and highlights the state of the art in tumor heterogeneity imaging.

Targeting the enzymes involved in arachidonic acid metabolism to improve radiotherapy.

During radiotherapy, an inflammatory response might be induced by activating various enzymes involved in membrane lipid metabolism. The eicosanoid pathway associated with cytosolic phospholipase A2 (cPLA2), cyclooxygenases (COXs), and lipoxygenases (LOXs) can be induced by radiation, and many lipid metabolites might contribute to cancer-associated inflammation, cell proliferation, and cell survival in cancer. The lipid metabolites are also involved in the establishment of the tumor-associated microenvironment through promotion of angiogenesis and formation of vascular network. These biological activities of lipid metabolites are responsible for malignant progression with the acquisition of radioresistance, leading to unsatisfactory outcome of cancer radiotherapy. Many efforts have been made to identify the mechanisms associated with bioactive lipid metabolites and radiation signaling that lead to radioresistance and to develop potent radiosensitizers to improve therapeutic efficacy. Beneficial outcomes would be achieved by targeting the enzymes, such as cPLA2, COXs, and LOXs, responsible for arachidonic acid metabolism and cancer-associated inflammation during cancer radiotherapy. The current study demonstrated a brief review for the radioresistant effects of bioactive lipid metabolites and their enzymes in cancer and the radiosensitizing effects of inhibitors for the enzymes on cancer therapy.

Tumor-associated Adipose Tissue Microenvironment Supports Tumor Progression

Tumor-associated Adipose Tissue Microenvironment Supports Tumor Progression

USP24 Induces IL‐6 in Tumor‐associated Microenvironment through stabilizing p300 and β‐TrCP to Promote the Malignancy of Lung Cancer

Our previous study indicated that increase in USP24 level in lung cancer facilitates lung cancer metastasis. Our recent study found that higher USP24 level was found in tumor‐associated microenvironment (TAM) than surrounding lung cancer cells in lung cancer patient specimens. USP24 level was significantly increased in M2‐macrophages. Knockdown of USP24 in M2‐macrophages decreased the migratory and chemotactic activity of lung cancer cells and angiogenetic ability of human umbilical vein endothelial cells (HUVEC) induced by M2‐derived conditioned medium. In vivo experiments also showed USP24 knockdown decreased M2‐macrophages induced lung cancer cells metastasis and angiogenesis. IL‐6 mRNA and protein levels were significantly decreased in USP24 knockdown M2‐macrophages and lung cancer cells. IL‐6 replenishment can rescue migratory and chemotactic ability of conditioned medium derived from USP24 knockdown M2‐macrophages, suggesting that increase in USP24 in M2‐macrophages induce the metastasis activity of lung through promoting IL‐6 expression. To address the molecular mechanism of how USP24 regulated IL‐6 in M2‐macrophage and lung cancer cells, we found that USP24 stabilized p300, thereby increased the transcriptional activity of IL‐6. USP24 could also decreased DNM1 and IkB level through stabilizing β‐TrCP and resulted in upregulated IL‐6. Metastatic cytokines in tumor‐associated microenvironment are important for cancer progression, in this study, we provide the direct evidence to support that USP24 increased in M2‐macrophages and lung cancer cells positive regulates the metastasis of lung cancer through enhancing the IL‐6 expression, which might be beneficial for the drug development for cancer therapy in the future.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2−/−) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2−/− mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2−/− macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2−/− macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.

USP24 Induces IL-6 in Tumor-associated Microenvironment through Stabilizing p300 and beta-TrCP to Promote the Malignancy of Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide. In particular,tumor metastasis is the most life-threatening event of lung cancer patients. More and more effective drugs for clinical use in cancer therapy have been developed up to now. However,the drug resistance is always occurred after drug treatment for a long time. Therefore,how to conquer the drug resistance during drug treatment is an important issue. Our preliminary result show that over expression of ubiquitin-specific peptidase 24 (USP24),a deubiquitinase,causes the cell apoptosis and abnormal mitosis progression,implying that USP24 might be involved in genomic instability. Therefore,we hypothesize that USP24 might induce genomic instability and drug resistance through mediating DNA damage repair activity. Our previous study indicated that increase in USP24 level in lung cancer facilitates lung cancer metastasis. Our recent study found that higher USP24 level was found in tumor-associated microenvironment (TAM) than surrounding lung cancer cells in lung cancer patient specimens. USP24 level was significantly increased in M2-macrophages. Knockdown of USP24 in M2-macrophages decreased the migratory and chemotactic activity of lung cancer cells and angiogenetic ability of human umbilical vein endothelial cells (HUVEC) induced by M2-derived conditioned medium. In vivo experiments also showed USP24 knockdown decreased M2-macrophages induced lung cancer cells metastasis and angiogenesis. IL-6 mRNA and protein levels were significantly decreased in USP24 knockdown M2-macrophages and lung cancer cells. IL-6 replenishment can rescue migratory and chemotactic ability of conditioned medium derived from USP24 knockdown M2-macrophages,suggesting that increase in USP24 in M2-macrophages induce the metastasis activity of lung through promoting IL-6 expression. To address the molecular mechanism of how USP24 regulated IL-6 in M2-macrophage and lung cancer cells, we found that USP24 stabilized p300, thereby increased the transcriptional activity of IL-6. USP24 could also decreased DNMT1 and Ikapa-B levels through stabilizing beta-TrCP and resulted in upregulated IL-6. Metastatic cytokines in tumor-associated microenvironment are important for cancer progression,in this study,we provide the direct evidence to support that USP24 increased in M2-macrophages and lung cancer cells positive regulates the metastasis of lung cancer through enhancing the IL-6 expression, which might be beneficial for the drug development for cancer therapy in the future.

Immunological landscape of consensus clusters in colorectal cancer.

Recent, large-scale expression–based subtyping has advanced our understanding of the genomic landscape of colorectal cancer (CRC) and resulted in a consensus molecular classification that enables the categorization of most CRC tumors into one of four consensus molecular subtypes (CMS). Currently, major progress in characterization of immune landscape of tumor-associated microenvironment has been made especially with respect to microsatellite status of CRCs. While these studies profoundly improved the understanding of molecular and immunological profile of CRCs heterogeneity less is known about repertoire of the tumor infiltrating immune cells of each CMS.In order to comprehensively characterize the immune landscape of CRC we re-analyzed a total of 15 CRC genome-wide expression data sets encompassing 1597 tumors and 125 normal adjacent colon tissues. After quality filtering, CRC clusters were discovered using a combination of multiple clustering algorithms and multiple validity metrics. CIBERSORT algorithm was used to compute relative proportions of 22 human leukocyte subpopulations across CRC clusters and normal colon tissue. Subsequently, differential expression specific to tumor epithelial cells was calculated to characterize mechanisms of tumor escape from immune surveillance occurring in particular CRC clusters.Our results not only characterize the common and cluster-specific influx of immune cells into CRCs but also identify several deregulated gene targets that may contribute to improvement of immunotherapeutic strategies in CRC.

VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN.

In lung adenocarcinoma, loss of p53 and PTEN in tumors are associated with decreased response to chemotherapy and decreased survival. A means to pharmacologically upregulate p53 and PTEN protein expression could improve the prognosis of patients with p53- and PTEN-deficient tumors. In the present study we revealed that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in lung adenocarcinoma cells was associated with improved expression levels of both p53 and PTEN in the tumor-associated macrophage (TAM) microenvironment. Inhibition of VEGFR3 in lung adenocarcinoma cells was associated with growth arrest and decreased migration and invasion. The upregulation of p53 and PTEN protein expression after VEGFR3 inhibition decreased chemotherapy resistance and improved chemosensitivity in co-cultured A549 cells in which p53 and PTEN expression were decreased. Finally, we demonstrated that TAMs promoted the expression of VEGF-C and its receptor VEGFR3. Western blot analysis revealed the co-cultured A549 cells with TAMs are a primary source of VEGF-C and VEGFR3 in the tumor microenvironment. Our studies revealed that VEGFR3 inhibition may be a pharmacological means to upregulate p53 and PTEN protein expression and improve the outcome of patients with p53- and PTEN-deficient tumors.

Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma

Tumor-associated inflammation plays a critical role in facilitating tumor growth, invasion and metastasis. Our previous study showed Aflatoxin G1 (AFG1) could induce lung adenocarcinoma in mice. Chronic lung inflammation associated with superoxide dismutase (SOD)-2 upregulation was found in the lung carcinogenesis. However, it is unclear whether tumor-associated inflammation mediates SOD-2 to contribute to cell invasion in AFG1-induced lung adenocarcinoma. Here, we found increased SOD-2 expression associated with vimentin, α-SMA, Twist1, and MMP upregulation in AFG1-induced lung adenocarcinoma. Tumor-associated inflammatory microenvironment was also elicited, which may be related to SOD-2 upregulation and EMT in cancer cells. To mimic an AFG1-induced tumor-associated inflammatory microenvironment in vitro, we treated A549 cells and human macrophage THP-1 (MΦ-THP-1) cells with AFG1, TNF-α and/or IL-6 respectively. We found AFG1 did not promote SOD-2 expression and EMT in cancer cells, but enhanced TNF-α and SOD-2 expression in MΦ-THP-1 cells. Furthermore, TNF-α could upregulate SOD-2 expression in A549 cells through NF-κB pathway. Blocking of SOD-2 by siRNA partly inhibited TNF-α-mediated E-cadherin and vimentin alteration, and reversed EMT and cell migration in A549 cells. Thus, we suggest that tumor-associated inflammation mediates SOD-2 upregulation through NF-κB pathway, which may contribute to EMT and cell migration in AFG1-induced lung adenocarcinoma.Introduction.

Abstract 5667: Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths worldwide. This is largely due to the existence of a subpopulation of stem-like cells present within the tumor, known as cancer stem cells (CSCs) that drive metastasis and chemoresistance. In addition, we have now come to realize that the tumor-associated microenvironment not only provides structural support for tumor development, but more importantly the microenvironment provides cues to CSCs that regulate their biological properties. Chemotherapy often leads to apoptosis of cancer cells, and in previous studies we have shown that tumor-associated macrophages (TAMs) exponentially increase following chemotherapy. We hypothesized that TAMs, in response to chemotherapy-induced apoptosis, secrete factors that potentiate PDAC chemoresistance. In line with this hypothesis, we show that monocyte-derived macrophages cultured in the presence of apoptotic PDAC cells polarize towards an M2 pro-tumor phenotype and secrete factors that render naïve PDAC cells, specifically CSCs, resistant to Gemcitabine- or Abraxane-induced apoptosis, irrespective of mutations in p53. Importantly, chemoresistant cells showed increased sphere formation capacity and increased tumorigenesis as measured in an extreme limiting dilution assay in nude mice, confirming an enrichment in CSCs. Moreover, using a syngeneic orthotropic in vivo model of PDAC, we were able to significantly augment the anti-tumor potential of Gemcitabine by pharmacologically eliminating TAMs using clodronate liposomes. To determine the mechanism by which TAMs promote PDAC chemoresistance, we performed proteomic analyses on macrophage conditioned media and identified several proteins specifically induced and secreted when macrophages were co-cultured with apoptotic PDAC cells, including 14-3-3 protein zeta/delta (14-3-3ζ), a major regulator of apoptotic cellular pathways. We present additional data to show that TAM-seceretd 14-3-3ζ promotes CSC chemoresistance. Taken together, the sum of these data highlight a unique regulatory mechanism by which chemotherapy-induced apoptosis acts as a switch to initiate a pro-tumor/anti-apoptotic mechanism in PDAC, challenging the idea that apoptosis of tumor cell is therapeutically beneficial, at least when immune sensor cells, such as macropahges, are present. Citation Format: Gabriele D'Errico, Mireia Vallespinos, Sonia Alcala, Sandra Valle, Laura Martin-Hijano, Bruno Sainz. Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5667. doi:10.1158/1538-7445.AM2017-5667

Trans-scirpusin A showed antitumor effects via autophagy activation and apoptosis induction of colorectal cancer cells.

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development.

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.