scholarly journals Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Guohao Wang ◽  
Junji Xu ◽  
Jiangsha Zhao ◽  
Weiqin Yin ◽  
Dayong Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Cells ◽  
Immune Surveillance ◽  
Therapeutic Vaccine ◽  
Treatment Resistance ◽  
Inverse Correlation ◽  
Cell Infiltration ◽  
T Cell Infiltration

AbstractCancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii17-ii18
Author(s):  
Apeng Chen ◽  
Yinan Jiang ◽  
Zhengwei Li ◽  
Xiangwei Xiao ◽  
Dean Yimlamai ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Protein Complexes ◽  
Immune Surveillance ◽  
Cell Infiltration ◽  
Binding Motif ◽  
T Cell Infiltration ◽  
Pathway Activation ◽  
Galectin 3 ◽  
Immunosuppressive Microenvironment

Abstract Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

scholarly journals Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1741 ◽  
Author(s):  
Lena Bohaumilitzky ◽  
Magnus von Knebel Doeberitz ◽  
Matthias Kloor ◽  
Aysel Ahadova
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Science Studies ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Hereditary Tumors ◽  
Mmr Deficiency

Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.

scholarly journals B7-H3 and B7-H4 expression in phyllodes tumors of the breast detected by RNA in situ hybridization and immunohistochemistry: Association with clinicopathological features and T-cell infiltration

Tumor Biology ◽  
2018 ◽  
Vol 40 (11) ◽  
pp. 101042831881503 ◽  
Author(s):  
Ga-Eon Kim ◽  
Nah Ihm Kim ◽  
Min Ho Park ◽  
Ji Shin Lee
Keyword(s):  
In Situ Hybridization ◽  
T Cell ◽  
Protein Expression ◽  
Messenger Rna ◽  
Immune Surveillance ◽  
Cell Infiltration ◽  
Stromal Compartment ◽  
Phyllodes Tumors ◽  
T Cell Infiltration

Phyllodes tumors are rare biphasic breast tumors with the potential for both local recurrence and distant metastasis. The aberrant expression of B7-H3 and B7-H4 B7 molecules could be potential targets for future development of immunotherapeutic approaches. This work was undertaken to evaluate the expression of B7-H3 and B7-H4 in phyllodes tumors and assess the association with the grade and clinical behavior of phyllodes tumors. In addition, the roles of B7-H3 and B7-H4 in the regulation of tumor immune surveillance were evaluated by assessing the relationship between B7-H3/B7-H4 expression and T-cell infiltration. The messenger RNA and protein expression of B7-H3/B7-H4 were determined by RNAscope in situ hybridization and immunohistochemistry, respectively, in 101 phyllodes tumors (60 benign, 26 borderline, and 15 malignant) using a tissue microarray. Immunohistochemistry for CD3 and CD8 was also performed. B7-H3 messenger RNA and protein appeared to be concentrated mainly in the stromal compartment of phyllodes tumors. However, B7-H4 messenger RNA and protein were undetectable in the stromal compartment of phyllodes tumors. Stromal B7-H3 messenger RNA and protein expression were noted in 10 (16.7%) and 31 (51.7%) of 60 benign phyllodes tumors, 12 (46.1%) and 20 (76.9%) of 26 borderline phyllodes tumors, and 10 (66.7%) and 13 (86.7%) of 15 malignant phyllodes tumors, respectively. Stromal B7-H3 messenger RNA and protein expression increased as phyllodes tumors progressed from benign to borderline and finally to the malignant grade (Pearson’s R = 0.411, p < 0.001 and Pearson’s R = 0.293, p = 0.003, respectively). The recurrence rate was higher in the stromal B7-H3 messenger RNA or protein-positive group than in the negative group, but this difference was not significant. Stromal B7-H3 protein expression inversely correlated with the densities of CD3+ and CD8+ T-cell infiltrates ( p = 0.001 and p = 0.027, respectively). These results suggest that B7-H3 is involved in the progression of phyllodes tumors and may contribute to their immune surveillance.

scholarly journals HLA-DR cancer cells expression correlates with T cell infiltration and is enriched in lung adenocarcinoma with indolent behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria-Fernanda Senosain ◽  
Yong Zou ◽  
Tatiana Novitskaya ◽  
Georgii Vasiukov ◽  
Aneri B. Balar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Early Stage ◽  
Cell Number ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Hla Dr

AbstractLung adenocarcinoma (ADC) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate whether CyTOF identifies cellular and molecular predictors of tumor behavior. We developed and validated a CyTOF panel of 34 antibodies in four ADC cell lines and PBMC. We tested our panel in a set of 10 ADCs, classified into long- (LPS) (n = 4) and short-predicted survival (SPS) (n = 6) based on radiomics features. We identified cellular subpopulations of epithelial cancer cells (ECC) and their microenvironment and validated our results by multiplex immunofluorescence (mIF) applied to a tissue microarray (TMA) of LPS and SPS ADCs. The antibody panel captured the phenotypical differences in ADC cell lines and PBMC. LPS ADCs had a higher proportion of immune cells. ECC clusters (ECCc) were identified and uncovered two ADC groups. ECCc with high HLA-DR expression were correlated with CD4+ and CD8+ T cells, with LPS samples being enriched for those clusters. We confirmed a positive correlation between HLA-DR expression on ECC and T cell number by mIF staining on TMA slides. Spatial analysis demonstrated shorter distances from T cells to the nearest ECC in LPS. Our results demonstrate a distinctive cellular profile of ECC and their microenvironment in ADC. We showed that HLA-DR expression in ECC is correlated with T cell infiltration, and that a set of ADCs with high abundance of HLA-DR+ ECCc and T cells is enriched in LPS samples. This suggests new insights into the role of antigen presenting tumor cells in tumorigenesis.

Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells

2020 ◽  
Vol 18 (10) ◽  
pp. 1589-1602 ◽  
Author(s):  
Jing Han ◽  
Zhen Jiang ◽  
Chennan Wang ◽  
Xin Chen ◽  
Rongqing Li ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Aurora A ◽  
T Cell Infiltration

scholarly journals Targeting Innate Immunity in Cancer Therapy

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 138
Author(s):  
Srikrishnan Rameshbabu ◽  
Brian W. Labadie ◽  
Anna Argulian ◽  
Akash Patnaik
Keyword(s):  
Innate Immunity ◽  
T Cell ◽  
Cancer Therapy ◽  
Immune Responses ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Cell Infiltration ◽  
T Cell Infiltration

The majority of current cancer immunotherapy strategies target and potentiate antitumor adaptive immune responses. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, with an aggregate response rate of approximately 20% to date across all malignancies. The success of therapeutic inhibition of programmed death protein 1 (PD-1), protein death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with immune checkpoint inhibitors (ICI) has been limited to “hot” tumors characterized by preexisting T cell infiltration, whereas “cold” tumors, which lack T cell infiltration, have not achieved durable benefit. There are several mechanisms by which “cold” tumors fail to generate spontaneous immune infiltration, which converge upon the generation of an immunosuppressive tumor microenvironment (TME). The role of the innate immune system in tumor immunosurveillance and generation of antitumor immune responses has been long recognized. In recent years, novel strategies to target innate immunity in cancer therapy have emerged, including therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs); the DNA sensing cGAS/STING pathway; nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRP3; and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). In addition, therapeutic modulation of key innate immune cell types, such as macrophages and natural killer cells, has been investigated. Herein, we review therapeutic approaches to activate innate immunity within the TME to enhance antitumor immune responses, with the goal of disease eradication in “cold” tumors. In addition, we discuss rational immune-oncology combination strategies that activate both innate and adaptive immunity, with the potential to enhance the efficacy of current immunotherapeutic approaches.

scholarly journals 740 Radiotherapy-activated NBTXR3 nanoparticles Increase CD8+ T cell infiltration and diversity in tumors, and modulate the immunopeptidome of cancer cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A771-A771
Author(s):  
Audrey Darmon ◽  
Ping Zhang ◽  
Jordan Da silva ◽  
Sebastien Paris
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Single Agent ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Mhc I ◽  
T Cell Infiltration ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
The Impact

BackgroundWhen exposed to radiotherapy (RT), NBTXR3 nanoparticles increase radiation dose deposition from within the cancer cells. NBTXR3 is intended for a single intratumor injection. Results from a phase II/III clinical trial in patients with locally advanced Soft Tissue Sarcoma demonstrated significant superiority and clinical benefits of NBTXR3 activated by RT compared to RT alone, and was well tolerated. NBTXR3 is currently being evaluated in several other tumors including head and neck, liver, and pancreatic cancer as a single agent or in combination with anti-PD1. Moreover, preclinical studies have demonstrated that NBTXR3 can produce a significant abscopal effect, whereas RT alone cannot. Here, we explored the impact of NBTXR3 activated by RT on CD8+ infiltrates and TcR repertoire diversity change, and the effect on the immunopeptidome of cancer cells.MethodsCT26 (murine colorectal cancer cells) were subcutaneously injected in BALB/c mice in one flank. Then, tumors were intratumorally injected with NBTXR3 (or vehicle) and irradiated 24 hours later with 4Gy per fraction for 3 consecutive days. Tumors were collected 3 days after the last RT fraction and immune cell infiltrates were measured using immunohistochemistry (IHC) and digital pathology. For TcR repertoire sequencing, the same workflow was followed, except cells were injected in both flanks. Only right tumors received treatment, while left tumors remained untreated. For immunopeptidome analysis, in vitro cells were irradiated by 4Gy. After one day, cells were collected for isolation and sequencing of MHC I-loaded peptides.ResultsIHC analyses showed a significant increase of CD8+ T cell infiltrates in tumors of mice treated with NBTXR3+RT, while RT alone had no significant effect. In addition, NBTXR3+RT treatment was able to increase TcR repertoire diversity, both in treated and untreated tumors, compared to RT alone. Finally, analysis of immunopeptidome showed that NBTXR3+RT changed the profile of MHC-I-loaded peptides.ConclusionsOur in vivo data indicate that NBTXR3+RT can modulate the microenvironment of treated tumors, leading to enhanced CD8+ T cell infiltration as well as modification of the TcR repertoire, both in treated and distant untreated tumors. These NBTXR3+RT-induced responses may be related to changes in the immunopeptidome of cancer cells triggered by this treatment.

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