ISG15 pathway knockdown reverses pancreatic cancer cell transformation and decreases murine pancreatic tumor growth via downregulation of PDL-1 expression
AbstractInterferon-stimulated gene 15 (ISG15) is a 15  kDa protein induced by type I interferons (IFN-α and IFN-β) and is a member of the ubiquitin-like superfamily of proteins. The ISG15 pathway is highly expressed in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), suggesting a potential role of the ISG15 pathway (free ISG1 5 and ISG15 conjugates) in pancreatic carcinogenesis. However, very little is known about how the ISG15 pathway may contribute to pancreatic tumorigenesis. In the current study, we demonstrate that ISG15 pathway knockdown reverses the KRAS-associated phenotypes ...
Source: Cancer Immunology, Immunotherapy - November 11, 2019 Category: Cancer & Oncology Source Type: research

Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression
This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was norma...
Source: Cancer Immunology, Immunotherapy - November 8, 2019 Category: Cancer & Oncology Source Type: research

Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers
AbstractCheckpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved...
Source: Cancer Immunology, Immunotherapy - November 7, 2019 Category: Cancer & Oncology Source Type: research

Arginase-1-based vaccination against the tumor microenvironment: the identification of an optimal T-cell epitope
We describe frequent T-cell-based immune responses against this epitope in patients with cancer, as well as in healthy donors. Furthermore, we show that Arg-1-specific T cells expand in response to the TH2 cytokine interleukin (IL)-4 without any specific stimulation. Arg-1-specific memory TH1 cells that respond to increased IL-4 concentration may, therefore, drive the immune response back into the TH1 pathway. Arg-1-specific T cells thus appear to have an important function in immune regulation. Because Arg-1 plays an important role in the immunosuppressive microenvironment in most cancers, an immune modulatory vaccination...
Source: Cancer Immunology, Immunotherapy - November 6, 2019 Category: Cancer & Oncology Source Type: research

Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity
AbstractGlioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade glio...
Source: Cancer Immunology, Immunotherapy - November 5, 2019 Category: Cancer & Oncology Source Type: research

Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
In this report, targeted single-cell RNA sequencing was performed on 5T4p17-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and β chain (TRB) genes. Full-lengthTRA andTRB sequences were cloned into lentiviral vectors and transduced into CD8+ T-cells from healthy donors. Redirected effector T-cell function against 5T4p17 was measured by cytotoxicity and cytokine release assays. Seven uniqueTRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8+ T-cells with transduction efficiencies from 59 to 89%. TCR-tran...
Source: Cancer Immunology, Immunotherapy - November 4, 2019 Category: Cancer & Oncology Source Type: research

Immunomodulation by Schwann cells in disease
AbstractSchwann cells are the principal glial cells of the peripheral nervous system which maintain neuronal homeostasis. Schwann cells support peripheral nerve functions and play a critical role in many pathological processes including injury-induced nerve repair, neurodegenerative diseases, infections, neuropathic pain and cancer. Schwann cells are implicated in a wide range of diseases due, in part, to their ability to interact and modulate immune cells. We discuss the accumulating examples of how Schwann cell regulation of the immune system initiates and facilitates the progression of various diseases. Furthermore, we ...
Source: Cancer Immunology, Immunotherapy - November 1, 2019 Category: Cancer & Oncology Source Type: research

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting
AbstractThe TAM receptors —TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocyto sis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic an...
Source: Cancer Immunology, Immunotherapy - October 29, 2019 Category: Cancer & Oncology Source Type: research

Lysyl oxidases: linking structures and immunity in the tumor microenvironment
AbstractThe lysyl oxidases (LOXs) are a family of enzymes deputed to cross-link collagen and elastin, shaping the structure and strength of the extracellular matrix (ECM). However, many novel “non-canonical” functions, alternative substrates, and regulatory mechanisms have been described and are being continuously elucidated. The activity of LOXs, therefore, appears to be integrated into a complex network of signals regulating many cell functions, including survival/proliferation/di fferentiation. Among these signaling pathways, TGF-β and PI3K/Akt/mTOR, in particular, cross-talk extensively with each ...
Source: Cancer Immunology, Immunotherapy - October 25, 2019 Category: Cancer & Oncology Source Type: research

Identification of prognostic genes in the acute myeloid leukemia immune microenvironment based on TCGA data analysis
This study aimed to elucidate the value of immune/stromal cell-associated genes for AML prognosis by integrated bioinformatics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and used the ESTIMATE algorithm to calculate immune scores and stromal scores; we then identified differentially expressed genes (DEGs) based on these scores. Overall survival analysis was applied to reveal common DEGs of prognostic value. Subsequently, we conducted a functional enrichment analysis, generated a protein –protein interaction (PPI) network and performed an interrelation analysis of immune syst...
Source: Cancer Immunology, Immunotherapy - October 24, 2019 Category: Cancer & Oncology Source Type: research

Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma
AbstractHepatic stellate cells (HSCs) are important stromal cells and pivotal mediators involved in the pathogenesis and immunosuppression of hepatocellular carcinoma (HCC). The liver has been demonstrated to be a site for accumulation of tumor-induced myeloid-derived suppressor cells (MDSCs). We previously reported that HSCs induced an increase in the number of MDSCs in HCC. However, how MDSCs are recruited in HCC remains largely unclear. In the present study, we found that HSC-conditioned medium (HSC-CM) induced bone marrow-derived cell and splenocyte migration, especially MDSC migration. Using chemokine-neutralizing ant...
Source: Cancer Immunology, Immunotherapy - October 23, 2019 Category: Cancer & Oncology Source Type: research

Autophagy inhibition induces the repolarisation of tumour-associated macrophages and enhances chemosensitivity of laryngeal cancer cells to cisplatin in mice
AbstractTumour-associated macrophages (TAMs) are the key components in the tumour microenvironment. TAMs have two major subtypes, M1 and M2. M1 macrophages are tumour inhibitory, while M2 macrophages are tumour promotive. Repolarising TAMs from M2 to M1 is a promising strategy in cancer treatment. M1 and M2 macrophages were generated from murine bone marrow-derived macrophages (BMDMs). We found that chloroquine (CQ), an autophagy inhibitor, was able to repolarise M2 macrophages to the anti-tumour M1 phenotype. The repolarised macrophages demonstrated higher phagocytotic activity towards Hep-2 laryngeal tumour cells and re-...
Source: Cancer Immunology, Immunotherapy - October 22, 2019 Category: Cancer & Oncology Source Type: research

Regulatory T cells induce CD4 − NKT cell anergy and suppress NKT cell cytotoxic function
ConclusionTregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4− NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 22, 2019 Category: Cancer & Oncology Source Type: research

Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response
AbstractDiffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT,  with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with t...
Source: Cancer Immunology, Immunotherapy - October 22, 2019 Category: Cancer & Oncology Source Type: research

Pembrolizumab for anaplastic thyroid cancer: a case study
We present the case of a patient withBRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4  weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked ex...
Source: Cancer Immunology, Immunotherapy - October 22, 2019 Category: Cancer & Oncology Source Type: research

Monocytes reprogrammed with lentiviral vectors co-expressing GM-CSF, IFN- α2 and antigens for personalized immune therapy of acute leukemia pre- or post-stem cell transplantation
AbstractAcute myeloid leukemia (AML) is the most common acute leukemia in adults and overall survival remains poor. Chemotherapy is the standard of care for intensive induction therapy. Patients who achieve a complete remission require post-remission therapies to prevent relapse. There is no standard of care for patients with minimal residual disease (MRD), and stem cell transplantation is a salvage therapy. Considering the AML genetic heterogeneity and the leukemia immune-suppressive properties, novel cellular immune therapies to effectively harness immunological responses to prevent relapse are needed. We developed a nov...
Source: Cancer Immunology, Immunotherapy - October 18, 2019 Category: Cancer & Oncology Source Type: research

Antisense targeting of CD47 enhances human cytotoxic T-cell activity and increases survival of mice  bearing B16 melanoma when combined with anti-CTLA4 and tumor irradiation
AbstractAntibodies targeting the T-cell immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA4) enhance the effectiveness of radiotherapy for melanoma patients, but many remain resistant. To further improve response rates, we explored combining anti-CTLA4 blockade with antisense suppression of CD47, an inhibitory receptor on T cells that limit T-cell receptor signaling and killing of irradiated target cells. Human melanoma data from The Cancer Genome Atlas revealed positive correlations between CD47 mRNA expression and expression of T-cell regulators including CTLA4 and its counter receptors CD80 and CD86. Antisense sup...
Source: Cancer Immunology, Immunotherapy - October 18, 2019 Category: Cancer & Oncology Source Type: research

Clinicopathologic significance of human leukocyte antigen class I expression in patients with stage II and III gastric cancer
AbstractHuman leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded byHLA genes, and beta-2-microglobulin ( β2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, β2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array met...
Source: Cancer Immunology, Immunotherapy - October 16, 2019 Category: Cancer & Oncology Source Type: research

Lenalidomide improves the therapeutic effect of an interferon- α-dendritic cell-based lymphoma vaccine
In conclusion, our data demonstrate that IFN-DC-based vaccination plus lenalidomide exert an additive therapeutic effect in xenochimeric mice bearing established lymphoma. These results may pave the way to evaluate this co mbination in the clinical ground. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 16, 2019 Category: Cancer & Oncology Source Type: research

Neoadjuvant cisplatin and paclitaxel modulate tumor-infiltrating T cells in patients with cervical cancer
AbstractResistance to chemotherapy is widely recognized as one of the major factors limiting therapeutic efficacy and influences clinical outcomes in patients with cancer. Many studies on various tumor types have focused on combining standard-of-care chemotherapy with immunotherapy. However, for cervical cancer, the role of neoadjuvant chemotherapy (NACT) on the local immune microenvironment is largely unexplored. We performed a pilot study on 13 primary cervical tumor samples, before and after NACT, to phenotype and enumerate tumor-infiltrating T-cell subpopulations using multiplex immunohistochemistry (CD3, CD8, FoxP3, K...
Source: Cancer Immunology, Immunotherapy - October 15, 2019 Category: Cancer & Oncology Source Type: research

Contribution of Fc γ receptor IIB to creating a suppressive tumor microenvironment in a mouse model
AbstractVarious immune cells are recruited in the tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities, play an important role in regulating tumor growth and metastasis. However, the contribution of humoral immune responses against tumors is poorly understood. Fc receptors constitute critical elements for the up- or downregulation of immune responses through immune complexes. Here, we examined the potential role of the inhibitory Fc receptor, Fc γ receptor IIB (FcγRIIB), in tumor immunity using a mouse model. Our findings indicated that tumor...
Source: Cancer Immunology, Immunotherapy - October 15, 2019 Category: Cancer & Oncology Source Type: research

Natural killer cells control metastasis via structural editing of primary tumors in mice
AbstractNatural killer (NK) cells are innate immune lymphocytes which express an array of activating and inhibitory receptors. These receptors bind a large spectrum of ligands, which are expressed on stressed, malignantly transformed or virally infected cells, as well as on bacterial, fungal, and parasitic pathogens. The decision on whether or not to kill the target is based on the integration of activating and inhibitory signals sent downstream from NK cell receptors. One of the most prominent NK cell activating receptor families is the family of natural cytotoxicity receptors (NCRs) which includes NKp30, NKp44, and NKp46...
Source: Cancer Immunology, Immunotherapy - October 13, 2019 Category: Cancer & Oncology Source Type: research

Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy
ConclusionsThese findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 12, 2019 Category: Cancer & Oncology Source Type: research

Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy
ConclusionsThese results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 10, 2019 Category: Cancer & Oncology Source Type: research

The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer
AbstractTumors and their surrounding area represent spatially organized “ecosystems”, where tumor cells and the immune contextures of the different compartments are in a dynamic interplay, with potential clinical impact. Here, we aimed to investigate the prognostic significance of peritumoral tertiary lymphoid structures (TLS) either alone or jointly with the intrat umoral densities and spatial distribution of CD8 + and CD163 + cells in breast cancer (BCa) patients. TLS were identified peritumorally, within the area distancing up to 5 mm from the infiltrative tumor border, count...
Source: Cancer Immunology, Immunotherapy - October 9, 2019 Category: Cancer & Oncology Source Type: research

Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy
AbstractAdoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a...
Source: Cancer Immunology, Immunotherapy - October 8, 2019 Category: Cancer & Oncology Source Type: research

PTPN3 expressed in activated T lymphocytes is a candidate for a non-antibody-type immune checkpoint inhibitor
AbstractIt has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting thePTPN3 expression in activated lymphocytes significantly augmented the proliferation,...
Source: Cancer Immunology, Immunotherapy - September 27, 2019 Category: Cancer & Oncology Source Type: research

Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy
AbstractIn the past decade, remarkable progress has been made in immunotherapy against cancer. Specifically, the introduction of immune checkpoint inhibitors has revolutionized the field. However, many patients are unable to benefit significantly from this treatment option. One of the major reasons for this is most likely the absence of an adequate tumor-specific T cell response in these patients. A way to circumvent this problem might be to combine immune checkpoint inhibitor treatment with new strategies to activate tumor-specific T cells. One such  strategy could be to activate and mature dendritic cells in situ. D...
Source: Cancer Immunology, Immunotherapy - September 26, 2019 Category: Cancer & Oncology Source Type: research

Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment
AbstractPancreatic cancer has been termed a ‘recalcitrant cancer’ due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate g rowth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown ...
Source: Cancer Immunology, Immunotherapy - September 24, 2019 Category: Cancer & Oncology Source Type: research

The BRCA2 mutation status shapes the immune phenotype of prostate cancer
AbstractDefects in DNA damage repair caused by mutations inBRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation betweenBRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eightBRCA2-mutated tumors in comparison with eightBRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyze...
Source: Cancer Immunology, Immunotherapy - September 23, 2019 Category: Cancer & Oncology Source Type: research

Conventional CARs versus modular CARs
AbstractThe clinical application of immune effector cells genetically modified to express chimeric antigen receptors (CARs) has shown impressive results including complete remissions of certain malignant hematological diseases. However, their application can also cause severe side effects such as cytokine release syndrome (CRS) or tumor lysis syndrome (TLS). One limitation of currently applied CAR T cells is their lack of regulation. Especially, an emergency shutdown of CAR T cells in case of life-threatening side effects is missing. Moreover, targeting of tumor-associated antigens (TAAs) that are not only expressed on tum...
Source: Cancer Immunology, Immunotherapy - September 21, 2019 Category: Cancer & Oncology Source Type: research

T cell engineering for adoptive T cell therapy: safety and receptor avidity
AbstractSince the first bone marrow transplantation, adoptive T cell therapy (ACT) has developed over the last 80  years to a highly efficient and specific therapy for infections and cancer. Genetic engineering of T cells with antigen-specific receptors now provides the possibility of generating highly defined and efficacious T cell products. The high sensitivity of engineered T cells towards their targets, ho wever, also bears the risk of severe off-target toxicities. Therefore, different safety strategies for engineered T cells have been developed that enable removal of the transferred cells in case of adverse event...
Source: Cancer Immunology, Immunotherapy - September 21, 2019 Category: Cancer & Oncology Source Type: research

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer
ConclusionsAnti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 18, 2019 Category: Cancer & Oncology Source Type: research

Induction of tumor-specific CD8 + cytotoxic T lymphocytes from na ïve human T cells by using Mycobacterium -derived mycolic acid and lipoarabinomannan-stimulated dendritic cells
AbstractThe main effectors in tumor control are the class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1+CD141+ appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1+CD141+ molecules with a cross-p...
Source: Cancer Immunology, Immunotherapy - September 17, 2019 Category: Cancer & Oncology Source Type: research

ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy
ConclusionsOur findings suggest that ANTXR1 is a promising candidate for preclinical and clinical evaluation for gastric adenocarcinoma immunotherapy. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 14, 2019 Category: Cancer & Oncology Source Type: research

Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature
ConclusionsLCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 12, 2019 Category: Cancer & Oncology Source Type: research

Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients
AbstractPatients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline...
Source: Cancer Immunology, Immunotherapy - September 12, 2019 Category: Cancer & Oncology Source Type: research

Desmoid tumors display a strong immune infiltration at the tumor margins and no PD-L1-driven immune suppression
AbstractDesmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, ...
Source: Cancer Immunology, Immunotherapy - September 11, 2019 Category: Cancer & Oncology Source Type: research

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma
AbstractImmunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cance...
Source: Cancer Immunology, Immunotherapy - September 9, 2019 Category: Cancer & Oncology Source Type: research

Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment
AbstractMyeloid-derived suppressor cells (MDSC) are present in most cancer patients where they are significant contributors to the immune suppressive tumor microenvironment (TME). The TME is a hostile locale due to deficiencies in oxygen (hypoxia) and nutrients, and the presence of reactive oxygen species (ROS). The survival of tumor cells within the TME is partially governed by two mechanisms: (1) Activation of the transcription factor Nuclear Factor Erythroid-derived 2-like 2 (Nrf2) which turns on genes that attenuate oxidative stress; and (2) The presence of High Mobility Group Box Protein-1 (HMGB1), a damage-associated...
Source: Cancer Immunology, Immunotherapy - September 9, 2019 Category: Cancer & Oncology Source Type: research

Presence of T cells directed against CD20-derived peptides in healthy individuals and lymphoma patients
In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN- γ production by PBMCs and spl...
Source: Cancer Immunology, Immunotherapy - September 7, 2019 Category: Cancer & Oncology Source Type: research

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer
ConclusionsThe frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases.  Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells  in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 5, 2019 Category: Cancer & Oncology Source Type: research

Independent expression of circulating and tissue levels of PD-L1: correlation of clusters with tumor metabolism and outcome in patients with non-small cell lung cancer
ConclusionPlasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical –pathological parameters, allow for the identification of clusters with different outcomes. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 3, 2019 Category: Cancer & Oncology Source Type: research

A phase II study of the L19IL2 immunocytokine in combination with dacarbazine in advanced metastatic melanoma patients
AbstractEngineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000  mg/m2 of body surface on day 1 of 21-day cycles) as single agen...
Source: Cancer Immunology, Immunotherapy - September 3, 2019 Category: Cancer & Oncology Source Type: research

An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation
AbstractRIG-I is a cytosolic RNA sensor that recognizes short 5 ′ triphosphate RNA, commonly generated during virus infection. Upon activation, RIG-I initiates antiviral immunity, and in some circumstances, induces cell death. Because of this dual capacity, RIG-I has emerged as a promising target for cancer immunotherapy. Previously, a sequence-optimized RIG-I agonist (termed M8) was generated and shown to stimulate a robust immune response capable of blocking viral infection and to function as an adjuvant in vaccination strategies. Here, we investigated the potential of M8 as an anti-cancer agent by analyzing its ab...
Source: Cancer Immunology, Immunotherapy - August 28, 2019 Category: Cancer & Oncology Source Type: research

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials
ConclusionsTreatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - August 27, 2019 Category: Cancer & Oncology Source Type: research

CD4 + T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models
AbstractIt is well recognized that CD4+ T cells may play an important role in immunosurveillance and immunotherapy against cancer. However, the details of how these cells recognize and eliminate the tumor cells remain incompletely understood. For the past 25  years, we have focused on how CD4+ T cells reject multiple myeloma cells in a murine model (MOPC315). In our experimental system, the secreted tumor-specific antigen is taken up by tumor-infiltrating macrophages that process it and present a neoepitope [a V region-derived idiotypic (Id) peptide] on MHC class II molecules to Th1 cells. Stimulated Th1 cells produce...
Source: Cancer Immunology, Immunotherapy - August 26, 2019 Category: Cancer & Oncology Source Type: research

Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer
In conclusion, ieTILs and strTILs were non-redundant biomarkers in HNSCC and should be evaluated separately. The identified prognostic markers should be evaluated for predictivity in ICB-treated patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - August 23, 2019 Category: Cancer & Oncology Source Type: research

Melanoma-conditioned medium promotes cytotoxic immune responses by murine bone marrow-derived monocytes despite their expression of ‘M2’ markers
AbstractMacrophages have been shown to infiltrate a wide range of malignancies and are often considered to promote tumour survival, growth and spread. However, the source and behaviour of discrete tumour-associated macrophage populations are still poorly understood. Here we show a novel method for the rational development of bone marrow-derived monocytes appropriate for the study of processes which involve the contribution of circulating inflammatory monocytes. We have shown that in response to tumour-conditioned medium, these cells upregulate CD206 and CD115, markers traditionally associated with M2-type macrophages. Trea...
Source: Cancer Immunology, Immunotherapy - August 23, 2019 Category: Cancer & Oncology Source Type: research

A VEGFR2 –MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice
AbstractMHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2 –MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis ...
Source: Cancer Immunology, Immunotherapy - August 19, 2019 Category: Cancer & Oncology Source Type: research