Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma

Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM.

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Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

Cancers ◽

10.3390/cancers13092184 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2184

Author(s):

Valentina Cazzetta ◽

Sara Franzese ◽

Claudia Carenza ◽

Silvia Della Bella ◽

Joanna Mikulak ◽

...

Keyword(s):

Liver Cancer ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Primary Liver Cancer ◽

Circulating Antigens ◽

Direct Cytotoxicity ◽

Immune Changes

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.

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Understanding the Role of Fibroblasts following a 3D Tumoroid Implantation for Breast Tumor Formation

Bioengineering ◽

10.3390/bioengineering8110163 ◽

2021 ◽

Vol 8 (11) ◽

pp. 163

Author(s):

Girdhari Rijal

Keyword(s):

Tumor Cells ◽

Breast Tumor ◽

Tumor Tissue ◽

Review Paper ◽

Cell Activity ◽

Tumor Formation ◽

Cancer Associated Fibroblasts ◽

Technical Challenge ◽

Signaling Systems

An understanding of the participation and modulation of fibroblasts during tumor formation and growth is still unclear. Among many speculates, one might be the technical challenge to reveal the versatile function of fibroblasts in tissue complexity, and another is the dynamics in tissue physiology and cell activity. The histology of most solid tumors shows a predominant presence of fibroblasts, suggesting that tumor cells recruit fibroblasts for breast tumor growth. In this review paper, therefore, the migration, activation, differentiation, secretion, and signaling systems that are associated with fibroblasts and cancer-associated fibroblasts (CAFs) after implantation of a breast tumoroid, i.e., a lab-generated tumor tissue into an animal, are discussed.

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Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial

Journal of Experimental Medicine ◽

10.1084/jem.20191712 ◽

2020 ◽

Vol 217 (9) ◽

Author(s):

Matthew J. Frank ◽

Michael S. Khodadoust ◽

Debra K. Czerwinski ◽

Ole A.W. Haabeth ◽

Michael P. Chu ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Tumor Cells ◽

Cell Lymphoma ◽

Cell Vaccine ◽

Autologous Tumor ◽

Mantle Cell ◽

T Cell Immune Responses

Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

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The role of CTLA-4 in the regulation of T cell immune responses

Immunology and Cell Biology ◽

10.1046/j.1440-1711.1999.00795.x ◽

1999 ◽

Vol 77 (1) ◽

pp. 1-10 ◽

Cited By ~ 146

Author(s):

Kathy D McCoy ◽

Graham Le Gros

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Immune Responses

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Drug-Loaded Liposomal Spherical Nucleic Acid as an Effective Cancer Nanovaccine

10.21203/rs.3.rs-1074689/v1 ◽

2021 ◽

Author(s):

Bo Deng ◽

Bing Ma ◽

Yingying Ma ◽

Pei Cao ◽

Xigang Leng ◽

...

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

Tumor Tissue ◽

Simple Strategy ◽

Spherical Nucleic Acid ◽

Animal Survival ◽

Cpg Oligonucleotides ◽

Specific Antigens ◽

Spherical Nucleic Acids ◽

Mouse Lymphoma

Abstract Background: Cancer nanovaccine has become a promising approach for cancer immunotherapy. The major challenge of cancer vaccines is limited efficacy caused by lack of desirable tumor specific antigens (TSA). Chemotherapeutics can trigger immunogenic cell death (ICD) and release TSAs, which initiate tumor-specific immune responses. However, ICD-triggered immune responses are usually not potent enough to eliminate the tumor cells. Herein, we developed liposomal spherical nucleic acids (SNA) that can simultaneously deliver and release doxorubicin (DOX) and CpG oligonucleotides upon biological stimuli in tumors to augment antitumor immune responses. Results: SNA nanoparticle increased DOX accumulation at the tumor tissue to induce tumor cells apoptosis and autophagy to activate both ICD-triggered and autophagy-mediated Th1-type immune responses. Meanwhile, CpG, which was co-delivered with DOX, functioned synergistically to potentiate the antitumor immune responses. These nanoparticles effectively inhibited tumor growth and extended animal survival of a mouse lymphoma model. Conclusions: This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors to improve immunotherapeutic efficacy of nanovaccines.

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The role of Interleukin-33 in the modulation of splenic T-cell immune responses after experimental ischemic stroke

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2019.576970 ◽

2019 ◽

Vol 333 ◽

pp. 576970 ◽

Cited By ~ 7

Author(s):

Wei Xiao ◽

Shuang Guo ◽

Lin Chen ◽

Yi Luo

Keyword(s):

Ischemic Stroke ◽

T Cell ◽

Immune Responses ◽

Interleukin 33 ◽

T Cell Immune Responses

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Clinical Relevance of Immune Checkpoints on Circulating Tumor Cells in Breast Cancer

Cancers ◽

10.3390/cancers12020376 ◽

2020 ◽

Vol 12 (2) ◽

pp. 376 ◽

Cited By ~ 6

Author(s):

Maria A. Papadaki ◽

Anastasios V. Koutsopoulos ◽

Panormitis G. Tsoulfas ◽

Eleni Lagoudaki ◽

Despoina Aggouraki ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Tumor Tissue ◽

Mononuclear Cells ◽

Immune Checkpoints ◽

Peripheral Blood Mononuclear ◽

Increased Risk

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC.

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The Role of Autophagy in Tumor Immunology—Complex Mechanisms That May Be Explored Therapeutically

Frontiers in Oncology ◽

10.3389/fonc.2020.603661 ◽

2020 ◽

Vol 10 ◽

Author(s):

Alana Serrano Campelo de Souza ◽

Letícia Boslooper Gonçalves ◽

Ana Paula Lepique ◽

Patrícia Savio de Araujo-Souza

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

Immune Escape ◽

Nk Cell ◽

Nutrient Deficiency ◽

Potential Interaction ◽

Migration And Invasion ◽

Inhibitory Molecules ◽

Cancer Immunotherapies

The tumor microenvironment (TME) is complex, and its composition and dynamics determine tumor fate. From tumor cells themselves, with their capacity for unlimited replication, migration, and invasion, to fibroblasts, endothelial cells, and immune cells, which can have pro and/or anti-tumor potential, interaction among these elements determines tumor progression. The understanding of molecular pathways involved in immune escape has permitted the development of cancer immunotherapies. Targeting molecules or biological processes that inhibit antitumor immune responses has allowed a significant improvement in cancer patient’s prognosis. Autophagy is a cellular process required to eliminate dysfunctional proteins and organelles, maintaining cellular homeostasis. Usually a process associated with protection against cancer, autophagy associated to cancer cells has been reported in response to hypoxia, nutrient deficiency, and oxidative stress, conditions frequently observed in the TME. Recent studies have shown a paradoxical association between autophagy and tumor immune responses. Tumor cell autophagy increases the expression of inhibitory molecules, such as PD-1 and CTLA-4, which block antitumor cytotoxic responses. Moreover, it can also directly affect antitumor immune responses by, for example, degrading NK cell-derived granzyme B and protecting tumor cells. Interestingly, the activation of autophagy on dendritic cells has the opposite effects, enhancing antigen presentation, triggering CD8+ T cells cytotoxic activity, and reducing tumor growth. Therefore, this review will focus on the most recent aspects of autophagy and tumor immune environment. We describe the dual role of autophagy in modulating tumor immune responses and discuss some aspects that must be considered to improve cancer treatment.

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