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The accumulation of mutated somatic cells due to the incompetency of body's immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body's internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Abstract Background PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. Methods We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. Results The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 (p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC (p = 0.68) and MD-Anderson (p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313–0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636–1.241; p = 0.487) and 1.939 (95% CI: 0.483–7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including “BMS-536924,” “linsitinib,” “NVP-TAE684,” “PLX-4720,” and “clonazepam.” Conclusions The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients.

There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field. [ABSTRACT FROM AUTHOR]

Background: PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. Methods: We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. Results: The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 (p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC (p = 0.68) and MD-Anderson (p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313–0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636–1.241; p = 0.487) and 1.939 (95% CI: 0.483–7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including "BMS-536924," "linsitinib," "NVP-TAE684," "PLX-4720," and "clonazepam." Conclusions: The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients. [ABSTRACT FROM AUTHOR]

Abstract Background Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. Methods A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan–Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. Results Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan–Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. Conclusions We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.

Background: Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified.Methods: A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms.Results: Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures.Conclusions: We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients. [ABSTRACT FROM AUTHOR]

The accumulation of mutated somatic cells due to the incompetency of body's immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumorspecific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific antitumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumortargeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloidderived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body's internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse. [ABSTRACT FROM AUTHOR]

• Sialic acid-binding immunoglobulin-like lectin 15 (Siglec15) is an immune checkpoint molecule that can inhibit T cell proliferation and have anti-tumor immunity. We explored the correlation between Siglct15 and the clinical features, mutation frequency, and prognosis of breast cancer. 122 upregulated and 11 downregulated genes between Siglet15-high and -low expression groups of 1109 breast invasive cancer samples (BRCA) obtained from the Cancer Genome Atlas (TCGA) were identified, and three BRCA subtypes (C1–C3) were characterized via consensus cluster plus analysis. The clinical characteristics, functional enrichments, immune environment, mutation frequency, and prognosis of the Siglec15-related BRCA subtypes were analyzed. C3 was characterized by the highest proportion of estrogen or progesterone receptor-positive tumors, the highest level of Siglec15 mRNA expression, the highest stromal score, the highest level of M2 macrophages, the lowest tumor mutational burden (TMB), and the most favorable prognosis. In contrast, C2 was characterized by the highest proportion of basal-like tumors, the highest immune score, the highest TMB, the lowest level of Siglec15 mRNA expression, and the worst prognosis. The p53 signaling pathway was upregulated in C2, while the PI3K-Akt pathway was upregulated in C3. Subtype C1 had features between C3 and C2. There was a very weak correlation between Siglec15 and programmed death-ligand 1 (PD-L1) in BRCA. Therefore, Siglet15 may represent a promising target for immunotherapy in patients with hormone receptor-positive BRCA expressing low levels of PD-L1. In conclusion, we identified three Siglec15-related subtypes of BRCA, helping us to understand the immunological function and significance of Siglec15 in the BRCA. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec15) is an immune checkpoint molecule that can inhibit T cell proliferation and have anti-tumor immunity. We explored the correlation between Siglct15 and the clinical features, mutation frequency, and prognosis of breast cancer. 122 upregulated and 11 downregulated genes between Siglet15-high and -low expression groups of 1109 breast invasive cancer samples (BRCA) obtained from the Cancer Genome Atlas (TCGA) were identified. Three subtypes (C1-C3) of BRCA based on Siglec15 were identified from TCGA datasets via consensus cluster plus analysis. The clinical characteristics, functional enrichments, immune environment, mutation frequency, prognosis were compared among these subgroups and were verified using GSE20685 and GSE31448 cohorts. C3 with highest level of Siglec15 expression was correlated with early tumor stage, hormone receptor-positive tumors, luminal A molecular subtype, lowest tumor mutational burden (TMB) score, lowest programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression, upregulated PI3K-Akt pathway and advantage of prognosis. C2 with lowest level of Siglec15 was associated with advanced stage, basal-like subtype, highest TMB score, highest PD-1 and PD-L1 expression, upregulated p53 signaling pathway and worse prognosis. Univariate and multivariate Cox regression analysis demonstrated that Siglec15-related subtype was an independent prognostic factor for breast cancer patients. Siglec15 related immunotherapy may be an important candidate for breast cancer patients especially for luminal subtype, independently of blockade of PD-1/PD-L1 immunotherapy. In conclusion, we identified three Siglec15-related subtypes of BRCA, helping us to understand the immunological function and significance of Siglec15 in the BRCA. [ABSTRACT FROM AUTHOR]

Keywords: malignant mesothelioma; tumor biology; preclinical models; immune environment; angiogenesis inhibitors; chemotherapy; immunotherapy; microRNA EN malignant mesothelioma tumor biology preclinical models immune environment angiogenesis inhibitors chemotherapy immunotherapy microRNA 1 2 2 06/16/20 20200612 NES 200612 Malignant mesothelioma, resistant to most currently available therapies, is associated with the lowest survival rates of any major cancer type. Although some activity of experimental approaches such as intrapleural pro-inflammatory cytokines was noted in the 1990s ([1]-[4]), chemotherapy-based therapies, surgery and radiotherapy dominated clinical research into mesothelioma treatment through the 1990s and 2000s. Malignant mesothelioma, tumor biology, preclinical models, immune environment, angiogenesis inhibitors, chemotherapy, immunotherapy, microRNA. [Extracted from the article]