Understanding Of Tumor Microenvironment Research Articles

Comprehensive analysis of endoplasmic reticulum stress related signature in head and neck squamous carcinoma

Head and neck squamous carcinoma (HNSC) is a prevalent malignant disease, with the majority of patients being diagnosed at an advanced stage. Endoplasmic reticulum stress (ERS) is considered to be a process that promotes tumorigenesis and impacts the tumor microenvironment (TME) in various cancers. The study aims to investigate the predictive value of ERS in HNSC and explore the correlation between ERS-related genes and TME. A series of bioinformatics analyses were carried out based on mRNA and scRNA-seq data from the TCGA and GEO databases. We conducted RT-qPCR and western blot to validate the signature, and performed cell functional experiments to investigate the in vitro biological functions of the gene. We identified 63 ERS-related genes that were associated with outcome and stage in HNSC. A three-gene signature (ATF6, TRIB3, and UBXN6) was developed, which presents predictive value in the prognosis and immunotherapy response of HNSC patients. The high-risk group exhibited a worse prognosis but may benefit from immunotherapy. Furthermore, there was a significant correlation between the signature and immune infiltration. In the high-risk group, fibroblasts were more active in intercellular communication, and more T cells were observed at the end of the sequential phase. The genes in the ERS-related signature were overexpressed in HNSC cells, and the knockdown of TRIB3 significantly inhibited cell proliferation and migration. This study established a novel ERS-related signature that has potential implications for HNSC therapy and the understanding of TME.

Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial–mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.Graphical

Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma.

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class-1+, CD204+, and programmed death ligand-1 [PD-L1+]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4+ T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4+, and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized.

Prognostic prediction based on histopathologic features of tumor microenvironment in colorectal cancer.

To automatically quantify colorectal tumor microenvironment (TME) in hematoxylin and eosin stained whole slide images (WSIs), and to develop a TME signature for prognostic prediction in colorectal cancer (CRC). A deep learning model based on VGG19 architecture and transfer learning strategy was trained to recognize nine different tissue types in whole slide images of patients with CRC. Seven of the nine tissue types were defined as TME components besides background and debris. Then 13 TME features were calculated based on the areas of TME components. A total of 562 patients with gene expression data, survival information and WSIs were collected from The Cancer Genome Atlas project for further analysis. A TME signature for prognostic prediction was developed and validated using Cox regression method. A prognostic prediction model combined the TME signature and clinical variables was also established. At last, gene-set enrichment analysis was performed to identify the significant TME signature associated pathways by querying Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes database. The deep learning model achieved an accuracy of 94.2% for tissue type recognition. The developed TME signature was found significantly associated to progression-free survival. The clinical combined model achieved a concordance index of 0.714. Gene-set enrichment analysis revealed the TME signature associated genes were enriched in neuroactive ligand-receptor interaction pathway. The TME signature was proved to be a prognostic factor and the associated biologic pathways would be beneficial to a better understanding of TME in CRC patients.

Necroptosis is Related to Anti-PD-1 Treatment Response and Influences the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma.

The latest research suggesting that necroptosis plays a vital role in immune response. However, the influence of necroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 26 necroptosis-related molecules in HNSCC and the influence of genome changes. We investigated HNSCC samples and determined that there are two necroptosis phenotypes in HNSCC cancer, and there are significant differences in cell infiltration characteristics and survival in different necroptosis phenotypes. We used the single‐sample gene set enrichment analysis to measure the level of necroptosis in patients with NecroticScore, we confirmed that the NecroticScore can predict the prognosis of HNSCC patients and the response to immunotherapy. Patients with a high NecroticScore are more sensitive to immunotherapy and have a better prognosis. Our study suggests a significant correlation between the expression imbalance of necroptosis-related molecules and suggests necroptosis plays an important role in modeling the TME. In addition, we construct a risk prediction model which could stratify patients with HNSCC and predict patient prognosis according to this necroptosis-related molecules. In conclusion, evaluating necroptosis modification patterns contributes to enhancing our understanding of TME and can guide more effective immunotherapy strategies.

An Analysis Regarding the Association Between Connexins and Colorectal Cancer (CRC) Tumor Microenvironment.

BackgroundGap junctions, as one of the major ways to maintain social connections between cells, are now considered as one of the potential regulators of tumor metastasis. However, to date, studies on the relationship between gap junctions and colorectal cancer (CRC) are limited.MethodsWe synthesized connexins-coding gene expression data from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as MEXPRESS database, Gene Set Cancer Analysis (GSCA) database, Human Protein Atlas (HPA) database, Tumor Immune Single Cell Hub (TISCH) database, Search Tool for Retrieval of Gene Interaction Relationships (STRING), and Cytoscape software, etc., to investigate the biological mechanisms that may be involved in connexins. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of GJA4.ResultsWe found that CRC patients can be divided into two connexin clusters and that patients in cluster C1 had shorter survival than in cluster C2. The infiltration of M1 macrophages and NK cells was lower in cluster C1, while the levels of M2 macrophages and immune checkpoints were higher, indicating an immunosuppressed state in cluster C1. In addition, the epithelial–mesenchymal transition (EMT) phenotype was significantly activated in cluster C1. We observed that GJA4 was up-regulated in colorectal cancer tissues, which was related to poor prognosis. It was mainly expressed in fibroblasts, but the expression levels in normal intestinal epithelial cells were low. Finally, we found that GJA4 was associated with M2 macrophages and may be a potential immunosuppressive factor.ConclusionWe found that there is a significant correlation between abnormal connexins expression and patients’ prognosis, and connexins play an important role in stromal-tumor interactions. Connexins, especially GJA4, can help enhance our understanding of tumor microenvironment (TME) and may guide more effective immunotherapeutic strategies.

Development of a Novel Immune Subtyping System Expanded with Immune Landscape and an 11-Gene Signature for Predicting Prostate Cancer Survival.

Background Nearly half of patients with prostate cancer will develop metastasis. Immunotherapy is currently a promising strategy for treating metastatic prostate cancer. This study aimed to construct an immune subtyping system and provide a more comprehensive understanding of tumor microenvironment. Methods Data were downloaded from TCGA database and cBioPortal database. Consensus clustering was used to identify immune subtypes. Immune features were scored by ESTIMATE and CIBERSORT. Efficacy of different subtypes in immunotherapy was predicted by TIDE tool. Immune landscape was delineated through “monocle.” Coexpressed gene modules were identified by weighted correlation network analysis. Univariate Cox regression analysis and LASSO analysis were applied to construct a prognostic model. Results Four immune subtypes (IS1 to IS4) were identified. Prognosis, mutation patterns, expression of immune genes, immune biomarkers, immunohistochemical biomarkers, and prediction efficacy of immunotherapy were significantly different among four immune subtypes. Five coexpressed gene modules were identified and an 11-gene prognostic model was constructed based on the modules. Conclusions The study developed a novel immune subtyping system and an 11-gene prognostic model of prostate cancer, which could guide personalized treatment and immunotherapy for patients with prostate cancer.

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies.

Endometrial stromal tumor (EST) is an uncommon and unusual mesenchymal tumor of the uterus characterized by multicolored histopathological, immunohistochemical, and molecular features. The morphology of ESTs is similar to normal endometrial stromal cells during the proliferative phase of the menstrual cycle. ESTs were first classified into benign and malignant based on the number of mitotic cells. However, recently WHO has divided ESTs into four categories: endometrial stromal nodules (ESN), undifferentiated uterine sarcoma (UUS), low-grade endometrial stromal sarcoma (LG-ESS), and high-grade endometrial stromal sarcoma (HG-ESS). HG-ESS is the most malignant of these categories, with poor clinical outcomes compared to other types. With advances in molecular biology, ESTs have been further classified with morphological identification. ESTs, including HG-ESS, is a relatively rare type of cancer, and the therapeutics are not being developed compared to other cancers. However, considering the tumor microenvironment of usual stromal cancers, the advance of immunotherapy shows auspicious outcomes reported in many different stromal tumors and non-identified uterine cancers. These studies show the high possibility of successful immunotherapy in HG-ESS patients in the future. In this review, we are discussing the background of ESTs and the BCOR and the development of HG-ESS by mutations of BCOR or other related genes. Among the gene mutations of HG-ESSs, BCOR shows the most common mutations in different ways. In current tumor therapies, immunotherapy is one of the most effective therapeutic approaches. In order to connect immunotherapy with HG-ESS, the understanding of tumor microenvironment (TME) is required. The TME of HG-ESS shows the mixture of tumor cells, vessels, immune cells and non-malignant stromal cells. Macrophages, neutrophils, dendritic cells and natural killer cells lose their expected functions, but rather show pro-tumoral functions by the matricellular proteins, extracellular matrix and other complicated environment in TME. In order to overcome the current therapeutic limitations of HG-ESS, immunotherapies should be considered in addition to the current surgical strategies. Checkpoint inhibitors, cytokine-based immunotherapies, immune cell therapies are good candidates to be considered as they show promising results in other stromal cancers and uterine cancers, while less studied because of the rarity of ESTs. Based on the advance of knowledge of immune therapies in HG-ESS, the new strategies can also be applied to the current therapies and also in other ESTs.

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer.

Simple SummaryBreast cancer (BC) is the most common malignant neoplasm in women and one of the leading causes of cancer death in women worldwide. Programmed death-ligand 1 (PD-L1) is becoming an emerging biomarker in BC in recent years. It has been correlated with worse outcomes in patients with hormone receptor positive, but it has a predictive role to guide response to systemic treatment in the triple-negative breast cancer (TNBC) subtype, especially in the metastatic setting. Immune checkpoint inhibitors are beginning to be a part of the treatment for many TNBC patients. However, more studies are needed in order to identify wherefore immunotherapy benefits TNBC patients regardless of PD-L1 status in the localized disease, but only offer an improvement for PD-L1 positivity expression in the advanced setting. The aim of this review is to analyze PD-L1 in all BC subtypes, including clinical trials with anti-PD-1/L1 and their results.Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors.

Prognostic Value of Immune-Related Multi-IncRNA Signatures Associated With Tumor Microenvironment in Esophageal Cancer.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. Hence, for a better understanding of tumor microenvironment and to seek for novel molecular targets for esophageal cancer, we performed related studies on two histopathological subtypes of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Bioinformatic analyses were conducted based on the RNA-seq, genomic mutation, and clinical data from TCGA and GEO cohorts. We clustered patients into high-immunity and low-immunity groups through the ssGSEA results. The ESTIMATE algorithm was used to evaluate the tumor microenvironment. Patients with high immunity in both ESCC and EAC had lower tumor purity and poor survival. Subsequently, CIBERSORT was performed to learn about the detailed difference of tumor-infiltrating lymphocytes (TILs) between high- and low-immunity patients. Specific increase of M2 macrophages and decrease of activated dendric cells can be observed in ESCC and EAC, respectively. The most enriched functions and pathways of high-immunity patients were immunoglobulin complex, MHC class II protein complex, and allograft rejection according to the GO terms and KEGG. Two prognostic immune-related multi-lncRNA risk models were constructed and validated by ROC curve and PCA in ESCC and EAC. High-risk patients in both subtypes had poor survival, advanced clinical characteristics, and higher drug susceptibility except cisplatin and sorafenib. In addition, the tumor mutation burden (TMB) was positively correlated with the risk level in the ESCC and EAC and showed distinct differences between the two subtypes. In summary, we comprehensively analyzed the tumor microenvironment for two subtypes of esophageal cancer, identified two multi-lncRNA signatures predictive for the prognosis, and explored the possibility of the signatures to forecast drug susceptibility as well as TMB for the first time. The findings may serve as a conceptual basis for innovative strategy of individualized immunotherapy for esophageal cancer.

Abstract 2978: Unique 3D organoids autologous TIL coculture platform enables high throughput immune-oncology drug response studies

Abstract Background: Cancer progression and response to therapy are governed by complex cellular interactions in the tumor microenvironment (TME). A better understanding of TME and the immune microenvironment requires robust experimental systems modeling patient specific immune interactions. Conventional 2D cultures lack in recapitulating 3D morphological structures and complex immune biology of native human tumors. A vastly heterogenous TME impacts patient treatment response. There is a dearth of 2D or 3D in vitro models that mimic in vivo diversity of TME, including infiltrating immune populations. 3D organoid cultures typically contain neoplastic epithelium and fail to retain syngeneic tumor-infiltrating lymphocytes (TILs) interactions vital for exhibiting a clinically significant drug response. Here we describe patient-derived xenograft (PDX) derived 3D organoid (PDXO) cultures with autologous TILs to avoid alloreactivity and simulate tumor specific immune response. The described model allows the evaluation of TIL infiltration and high throughput screening of immune-modulatory therapies. Methods: Patient-derived xenografts from mice were enzymatically digested to establish PDXO. PDXO were characterized for expression of cancer specific cell-surface markers. TILs were expanded in culture from PBMCs from matching patients and characterized using flow cytometry. Organoids and TILs from the same patient were fluorescently labeled and cocultured for four days, and tumor infiltration and drug cytotoxicity with and without immune-therapeutics was evaluated. CellInsight CX7 high content imaging platform was used to track TILs, and cancer cells, and TIL infiltration was confirmed via immunofluorescence. Luminex technology was used to quantify changes in the cytokine profile upon drug treatment. Results: PDXO were established to mimic in vivo tumor biology. Tumor-specific TILs were expanded and characterized for expression of memory, inhibitory, proliferation, and regulatory T cell markers. TIL infiltration in organoids was observed from day one in culture and maintained over four days. Immunofluorescence for T cell marker CD3 (cluster of differentiation 3) within PDXO confirmed TIL infiltration. Infiltrating TILs and tumor cell killing evaluation using fluorescent dyes via high throughput imaging platform showed disease and patient-specific response. PDXO treatment with immune-modulatory therapeutics led to changes in the secreted levels of cytokines IL2 (interleukin 2), IFNγ (interferon gamma), and TNFα (tumor necrotic factor alpha). Conclusion: Our patient autologous TILs - PDXO culture platform can be used for high throughput drug screening to model immune-therapeutic response with the tumor specific immune microenvironment. Citation Format: Garima Kaushik, Padma Kamineny, Amy Wesa. Unique 3D organoids autologous TIL coculture platform enables high throughput immune-oncology drug response studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2978.

Mining TCGA database for gene expression in ovarian serous cystadenocarcinoma microenvironment.

BackgroundOvarian cancer is one of the leading causes of female deaths worldwide. Ovarian serous cystadenocarcinoma occupies about 90% of it. Effective and accurate biomarkers for diagnosis, outcome prediction and personalized treatment are needed urgentlyMethodsGene expression profile for OSC patients was obtained from the TCGA database. The ESTIMATE algorithm was used to calculate immune scores and stromal scores of expression data of ovarian serous cystadenocarcinoma samples. Survival results between high and low groups of immune and stromal score were compared and differentially expressed genes (DEGs) were screened out by limma package. The Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and the protein-protein interaction (PPI) network analysis were performed with the g:Profiler database, the Cytoscape and Search Tool for the Retrieval of Interacting Genes (STRING-DB). Survival results between high and low immune and stromal score groups were compared. Kaplan-Meier plots based on TCGA follow up information were generated to evaluate patients’ overall survival.ResultsEighty-six upregulated DEGs and one downregulated DEG were identified. Three modules, which included 49 nodes were chosen as important networks. Seven DEGs (VSIG4, TGFBI, DCN, F13A1, ALOX5AP, GPX3, SFRP4) were considered to be correlated with poor overall survival.ConclusionSeven DEGs (VSIG4, TGFBI, DCN, F13A1, ALOX5AP, GPX3, SFRP4) were correlated with poor overall survival in our study. This new set of genes can become strong predictor of survival, individually or combined. Further investigation of these genes is needed to validate the conclusion to provide novel understanding of tumor microenvironment with ovarian serous cystadenocarcinoma prognosis and treatment.

Implementation of a Novel Web-Based Lesion Selection Tool to Improve Acquisition of Tumor Biopsy Specimens.

For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections. Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups. The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy. The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted.

A Prognostic Microenvironment-Related Immune Signature via ESTIMATE (PROMISE Model) Predicts Overall Survival of Patients With Glioma.

ObjectiveIn the development of immunotherapies in gliomas, the tumor microenvironment (TME) needs to be investigated. We aimed to construct a prognostic microenvironment-related immune signature via ESTIMATE (PROMISE model) for glioma.MethodsStromal score (SS) and immune score (IS) were calculated via ESTIMATE for each glioma sample in the cancer genome atlas (TCGA), and differentially expressed genes (DEGs) were identified between high-score and low-score groups. Prognostic DEGs were selected via univariate Cox regression analysis. Using the lower-grcade glioma (LGG) data set in TCGA, we performed LASSO regression based on the prognostic DEGs and constructed a PROMISE model for glioma. The model was validated with survival analysis and the receiver operating characteristic (ROC) in TCGA glioma data sets (LGG, glioblastoma multiforme [GBM] and LGG+GBM) and Chinese glioma genome atlas (CGGA). A nomogram was developed to predict individual survival chances. Further, we explored the underlying mechanisms using gene set enrichment analysis (GSEA) and Cibersort analysis of tumor-infiltrating immune cells between risk groups as defined by the PROMISE model.ResultsWe obtained 220 upregulated DEGs and 42 downregulated DEGs in both high-IS and high-SS groups. The Cox regression highlighted 155 prognostic DEGs, out of which we selected 4 genes (CD86, ANXA1, C5AR1, and CD5) to construct a PROMISE model. The model stratifies glioma patients in TCGA as well as in CGGA with distinct survival outcome (P<0.05, Hazard ratio [HR]>1) and acceptable predictive accuracy (AUCs>0.6). With the nomogram, an individualized survival chance could be predicted intuitively with specific age, tumor grade, Isocitrate dehydrogenase (IDH) status, and the PROMISE risk score. ROC showed significant discrimination with the area under curves (AUCs) of 0.917 and 0.817 in TCGA and CGGA, respectively. GSEA between risk groups in both data sets were significantly enriched in multiple immune-related pathways. The Cibersort analysis highlighted four immune cells, i.e., CD 8 T cells, neutrophils, follicular helper T (Tfh) cells, and Natural killer (NK) cells.ConclusionsThe PROMISE model can further stratify both LGG and GBM patients with distinct survival outcomes.These findings may help further our understanding of TME in gliomas and shed light on immunotherapies.

Overall Survival Of Extraosseous Plasmacytoma: An Updated Analysis Of National Cancer Institute Database

Abstract Introduction/Objective Plasma cell neoplasms arising outside of bone are known as extraosseous/extramedullary plasmacytoma. Although they constitute about 1% of all plasma cell neoplasms, updated epidemiological data are lacking in the current literature. Here, we have analyzed the incidence provided by the national cancer institute (SEER database) from 1975 – 2016 to shed light on the incidence, demographics, and survival of extraosseous plasma cell neoplasms. Methods We selected all cases of plasma cell neoplasms from the data provided by the national cancer institute (SEER database) from 1975 – 2016. We excluded all cases designated with the primary site as bone or bone marrow. We analyzed the data using SPSS statistics 20. We compared overall survival among different demographic groups and performed the log-rank test to see differences in overall survival. Results A total of 731 cases were found with extraosseous plasmacytoma in the United States with a male: female ratio of 1.85:1. The age range was from 9 to 92 years with a median age of 61. Younger age of diagnosis was associated with better overall survival. Overall survival was not significantly different between males and females (p = 0.4). The majority of the patients were Caucasian and overall survival was significantly better in this group (p = 0.028). Consistent with the current literature, the primary sites of the majority of cases were head and neck (44.5%) and soft tissue (15.7%). Overall survival was significantly different between different primary sites (p &amp;lt; 0.05) with primary sites of soft tissue, thorax (including lung, mediastinum, and pleura), and CNS showing particularly poor survival. Conclusion Our results suggest that the prognosis of extraosseous plasma cell neoplasm is site-specific and a better understanding of tumor microenvironment in plasmacytoma arising in different primary sites is warranted.

Intrastromal Therapy In-sync with Featured Stereotactic Body Radiotherapy (SBRT)-Fixing the Defiant Tumor Microenvironment-A Proof of Concept Study

The past decade has thrown much light over understanding of tumor micro-environment and its effects on cancer immune evasion. Fibroblasts are resting mesenchymal cells that can be activated to facilitate tissue repair during wound healing. However, cancer associated fibroblasts (CAF) are functionally intense. CAFs can produce growth factors and cytokines such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) to promote angiogenesis and recruit immuno-suppressive cells into the tumor stroma leading to immune evasion .Our study targets this resistant tumor stroma using actinium tagged Fibroblast activation protein(FAP) imaging followed by a phased SBRT to one or more sites, Thus by modulating the CAF associated tumor immune-tolerance an improved neo-antigen presentation during SBRT could be expected which may lead to better response rates. The study was started after institutional ethical clearance. A total of 5 patients with disseminated metastatic disease who have had first line therapies and failed subsequently on multiple lines of chemotherapy/targeted therapy were recruited post informed consent. A diagnostic actinium tagged FAP imaging was done and on confirmation of the FAPs tumor site uptake, therapeutic doses of Actinium tagged with FAPs to a dose of 300 micro grams Intravenous. Post 5 days of intra-stromal therapy, SBRT was given in 3 to 5 fractions to the core of all visible metastatic lesions. Patients were assessed for response after 6 weeks with a PET-CT and the side effect profile was assessed with liver function tests, kidney function tests at one-week post completion of SBRT (Stereotactic body Radiotherapy) and also at 6 weeks prior to response assessment PET-CT scan. In all the five patients, there were no observed toxicity with respect to the liver and kidney at 1 week and at 6 weeks post therapy. See Table.Abstract 192; TablePR-Partial response, CR-Complete response, SD-Stable DiseasePrimaryRadiationSiteDoseResponse (RT Site)Response (Distant Site)Patient 1BreastSBRT-3 FractionsBone24GyPRPRPatient 2OvarySBRT-3 FractionsLiver36GyCRPRPatient 3ProstateSBRT-5 FractionsBone35GyPRPRPatient 4ProstateSBRT-3 FractionsProstate24GyPRSDPatient 5LungSBRT-5 FractionsLung30GyPRPR Open table in a new tab Evolution of robust treatment strategies targeting tumor microenvironment is a field of exciting research. Effectively tackling the tumor immune evasion mechanisms based on individual tumor microenvironment profiling such as FAP imaging would ultimately aid in improved response to therapy. The early results of our study are encouraging.

Characterization of the Immune Cell Infiltration Landscape in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy

The tumor microenvironment (TME) chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with the stromal component. A recent clinical trial has shown that the tumor immune cell infiltration (ICI) is correlated with the sensitivity to immunotherapy and the head and neck squamous cell carcinoma (HNSC) prognosis. However, to date, the immune infiltrative landscape of HNSC has not yet been elucidated. Herein, we proposed two computational algorithms to unravel the ICI landscape of 1,029 HNSC patients. Three ICI patterns were defined, and the ICI scores were determined by using principal-component analysis. A high ICI score was characterized by an increased tumor mutation burden (TMB) and the immune-activating signaling pathways. Activation of transforming growth factor-β (TGF-β) and WNT signaling pathways were observed in low ICI score subtypes, indicating T cell suppression, and may be responsible for poor prognosis. Two immunotherapy cohorts confirmed patients with higher ICI scores demonstrated significant therapeutic advantages and clinical benefits. This study demonstrated that the ICI scores serve as an effective prognostic biomarker and predictive indicator for immunotherapy. Evaluating the ICI patterns of a larger cohort of samples will extend our understanding of TME, and it may provide directions to the current research investigations on immunotherapeutic strategies for HNSC.

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma.

Soft tissue sarcomas (STS) account for less than 1% of adult cancers with a median overall survival of 12 months in the metastatic setting. Although chemotherapy remains the standard of treatment for advanced disease, molecular targeted agents (MTAs) and immunotherapies are under intensive investigation in STS. The success of MTAs comes mainly from antiangiogenic agents in various STS subtypes, from colony-stimulating factor-1 receptor inhibitor in tenosynovial giant cell tumor and neurotrophic tropomyocin receptor kinase (NTRK) inhibitors while others, such as cyclin-dependent kinase (CDK)-4 inhibitors, remain under evaluation. In advanced STS the activity of single-agent immunotherapy was not paradigm-changing as in other tumor types. A better understanding of tumor microenvironment, the immunogenic properties of MTAs, and finding an optimal treatment combination to improve patients outcomes became a central topic of research and discussion. Furthermore, the development and incorporation of transcriptomic profiling-based classification will allow identification, refined patient selection, and guided-treatment assignment. This article reviewed recent advances in STS treatment in MTAs and immunotherapy, strategies to overcome resistance, and outcomes of combination treatments in different STS subtypes. Promising preliminary results from combination strategies have shed light on STS treatment. The increasing understanding of this heterogeneous group of tumors and its microenvironment biology may help develop and guide treatment strategies with MTA and immunotherapies, alone or in combination, in a tailored way based on predictive and validated biomarkers and tumor molecular profiling in this new coming era.

Strategies for Targeting Cancer Immunotherapy Through Modulation of the Tumor Microenvironment

Cancer immunotherapeutic strategies have shifted the focus of cancer treatment from eradicating the tumor cell by conventional cytotoxic chemotherapy, to educating the immune system to eliminate tumor, thereby preventing the recurrence of cancer. The understanding of tumor microenvironment and its components which generate an immunosuppressive environment is critical in further developing efficient immunotherapies. In this review, we have classified the current immunotherapies based on their effect in modulating the tumor microenvironment. Additionally, we propose the inclusion of nanotechnology and tissue engineering approaches, which provide unique strategies to enhance the therapeutic efficacy and could lead to developing nano/engineered immunotherapies for improved clinical outcomes. Specifically, we focus on criteria for designing nano/engineered immunotherapies and discuss targeted delivery strategies that can optimize the bioavailability of immunotherapies and, in turn, improve the therapeutic outcomes in the treatment of cancer. Several strategies aimed to exploit the therapeutic benefits of immunotherapy are based on alterations of the complex immunosuppressive tumor microenvironment. Such targeted approaches have also been significantly improved by various design criteria based on the concepts of nanotechnology and tissue engineering. The properties of specific targeting, controlled release, and ability to attain enhanced therapeutic effects with low doses conferred by these approaches have immensely helped to surmount the side effects and off-target issues of existing methods. Incorporation of these design criteria while developing various carrier systems for targeted immunotherapy would certainly enhance their clinical translation potential, eventually augmenting anti-tumor responses. Modulation of tumor microenvironment with strategies discussed in this review will provide additional opportunities to improve cancer immunotherapy, especially in challenging diseases such as pancreatic and brain tumors. Various design attributes with targeted systems would provide numerous advantages, widening the scope of clinical translation and benefits to cancer patients.

Overview of Microsatellite Instability and Immune Checkpoint Inhibitors in Colorectal Cancer

This review examines the pathophysiological features of microsatellite instability (MSI) high colorectal cancer and discusses recent clinical studies of immune checkpoint inhibitors for MSI high colorectal cancer. Emerging clinical data demonstrated durable clinical activity and safety of PD-1 blockade agents in diverse cancers, and PD-1 blockade agents have led to a paradigm shift in the cancer therapy. Although initial clinical data showed disappointing result of anti-PD-1 therapy in unselected metastatic colorectal cancer, recent data demonstrated promising results with significant anticancer activity of PD-1 blockade in colorectal cancers with microsatellite instability which have highly immunogenic tumor microenvironment. Anti-PD-1 therapy demonstrated durable clinical activity and safety, and it has changed the landscape of cancer therapy in MSI high colorectal cancer. Further studies with better understanding of tumor microenvironment will improve clinical outcomes of colorectal cancer.