scholarly journals Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1920
Author(s):  
Alvaro Morales-Molina ◽  
Miguel Ángel Rodríguez-Milla ◽  
Alicia Gimenez-Sanchez ◽  
Ana Judith Perisé-Barrios ◽  
Javier García-Castro
Keyword(s):  
Mouse Models ◽  
Tumor Infiltrating Lymphocytes ◽  
Oncolytic Viruses ◽  
Lower Percentage ◽  
Human Clinical Trial ◽  
Renal Adenocarcinoma ◽  
Clinical Responses ◽  
Induced Changes ◽  
Infiltrating Lymphocytes ◽  
Cell Death Protein

Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)—the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer.

scholarly journals Characterization of Ex Vivo Expanded Tumor Infiltrating Lymphocytes from Patients with Malignant Melanoma for Clinical Application

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Niels Junker ◽  
Per thor Straten ◽  
Mads Hald Andersen ◽  
Inge Marie Svane
Keyword(s):  
Malignant Melanoma ◽  
Specific Activity ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Effector Memory ◽  
Autologous Tumor ◽  
Advanced Malignant Melanoma ◽  
Clinical Responses ◽  
Infiltrating Lymphocytes

Clinical trials of adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) to patients with advanced malignant melanoma have shown remarkable results with objective clinical responses in 50% of the treated patients. In order to initiate a clinical trial in melanoma, we have established a method for expanding TILs to clinical relevant quantities in two steps with in 8 weeks. Further characterization of expanded TILs revealed an oligoclonal composition of T-cells with an effector memory like phenotype. When autologous tumor was available, TILs showed specific activity in all patients tested. TIL cultures contained specificity towards tumor cells as well as peptides derived from tumor-associated antigens (TAAs) during expansion procedures.

scholarly journals Strategies to package recombinant Adeno-Associated Virus expressing the N-terminal gasdermin domain for tumor treatment

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuan Lu ◽  
Wenbo He ◽  
Xin Huang ◽  
Yu He ◽  
Xiaojuan Gou ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Oncolytic Viruses ◽  
Tumor Treatment ◽  
Adeno Associated Virus ◽  
Robust Immune Response ◽  
Cancer Models ◽  
Infiltrating Lymphocytes ◽  
Oncolytic Effect

AbstractPyroptosis induced by the N-terminal gasdermin domain (GSDMNT) holds great potential for anti-tumor therapy. However, due to the extreme cytoxicity of GSDMNT, it is challenging to efficiently produce and deliver GSDMNT into tumor cells. Here, we report the development of two strategies to package recombinant adeno-associated virus (rAAV) expressing GSDMNT: 1) drive the expression of GSDMNT by a mammal specific promoter and package the virus in Sf9 insect cells to avoid its expression; 2) co-infect rAAV-Cre to revert and express the double-floxed inverted GSDMNT. We demonstrate that these rAAVs can induce pyroptosis and prolong survival in preclinical cancer models. The oncolytic-viruses induce pyroptosis and evoke a robust immune-response. In a glioblastoma model, rAAVs temporarily open the blood-brain barrier and recruit tumor infiltrating lymphocytes into the brain. The oncolytic effect is further improved in combination with anti-PD-L1. Together, our strategies efficiently produce and deliver GSDMNT into tumor cells and successfully induce pyroptosis, which can be exploited for anti-tumor therapy.

scholarly journals Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting

2016 ◽  
Vol 10s1 ◽  
pp. CMO.S34540 ◽  
Author(s):  
Paula García-Teijido ◽  
María Luque Cabal ◽  
Ignacio Peláez Fernández ◽  
Yolanda Fernández Pérez
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Immune System ◽  
Programmed Cell Death ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
Infiltrating Lymphocytes ◽  
Cell Death Protein

Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials.

scholarly journals The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature

2021 ◽  
Vol 22 (2) ◽  
pp. 843
Author(s):  
Jan Korbecki ◽  
Klaudyna Kojder ◽  
Patrycja Kapczuk ◽  
Patrycja Kupnicka ◽  
Barbara Gawrońska-Szklarz ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Hypoxia Inducible Factor ◽  
Suppressor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Therapies ◽  
Hypoxia Inducible Factor 1 ◽  
Cxc Chemokine ◽  
Induced Changes ◽  
Available Information ◽  
Infiltrating Lymphocytes

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.

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