scholarly journals Cowpea Mosaic Virus Nanoparticle Enhancement of Hypofractionated Radiation in a B16 Murine Melanoma Model

2020 ◽  
Vol 10 ◽  
Author(s):  
Kayla E. A. Duval ◽  
Robert J. Wagner ◽  
Veronique Beiss ◽  
Steven N. Fiering ◽  
Nicole F. Steinmetz ◽  
...  
Keyword(s):  
Single Dose ◽  
T Cell ◽  
Protein Expression ◽  
Tumor Growth ◽  
Mosaic Virus ◽  
Cowpea Mosaic Virus ◽  
T Cell Infiltration ◽  
Anti Cancer ◽  
Melanoma Model ◽  
Hypofractionated Radiation

IntroductionVirus and virus-like nanoparticles (VNPs) have been used for a variety of preclinical treatments, including in situ anti-cancer vaccination. The Cowpea mosaic virus (CPMV) is a VNP that has shown the ability to stimulate an anti-cancer immune response. The hypothesis of this study is two-fold: that intratumoral CPMV enhances the immunogenetic and cytotoxic response of hypofractionated radiation (15 Gy or 3 x 8 Gy), and that the effect differs between fraction regimens in the murine B16 flank melanoma model.MethodsCPMV nanoparticles were delivered intratumorally, 100 μg/tumor to B16 murine melanoma flank tumors alone, and in combination with either 15 Gy or 3 x 8 Gy (3 consecutive days). Tumors were assessed for immune and cytotoxic gene and protein expression, and cytotoxic T cell infiltration 4 days post treatment. Treatment based tumor control was assessed by a 3-fold tumor growth assay.ResultsBoth CPMV and radiation alone demonstrated the activation of a number of important immune and cytotoxic genes including natural killer cell and T cell mediated cytotoxicity pathways. However, the combination treatment activated greater expression than either treatment alone. CPMV combined with a single dose of 15 Gy demonstrated greater immune and cytotoxic gene expression, protein expression, CD8+ T cell infiltration activity, and greater tumor growth delay compared to 3 x 8 Gy with CPMV.ConclusionCPMV presents a unique and promising hypofractionated radiation adjuvant that leads to increased anti-tumor cytotoxic and immune signaling, especially with respect to the immune mediated cytotoxicity, immune signaling, and toll-like receptor signaling pathways. This improvement was greater with a single dose than with a fractionated dose.

scholarly journals Immune Responses Raised in an Experimental Colon Carcinoma Model Following Oral Administration of Lactobacillus casei

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 368 ◽  
Author(s):  
Georgios Aindelis ◽  
Angeliki Tiptiri-Kourpeti ◽  
Evangeli Lampri ◽  
Katerina Spyridopoulou ◽  
Eleftheria Lamprianidou ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Oral Administration ◽  
Tumor Growth ◽  
Colon Carcinoma ◽  
Lactobacillus Casei ◽  
Tumor Tissue ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Anti Cancer

The role of dietary probiotic strains on host anti-cancer immune responses against experimental colon carcinoma was investigated. We have previously shown that Lactobacillus casei administration led to tumor growth suppression in an experimental colon cancer model. Here, we investigated the underlying immune mechanisms involved in this tumor-growth inhibitory effect. BALB/c mice received daily live lactobacilli per os prior to the establishment of a syngeneic subcutaneous CT26 tumor. Tumor volume, cytokine production, T cell differentiation and migration, as well as tumor cell apoptosis were examined to outline potential immunomodulatory effects following L. casei oral intake. Probiotic administration in mice resulted in a significant increase in interferon gamma (IFN-γ), Granzyme B and chemokine production in the tumor tissue as well as enhanced CD8+ T cell infiltration, accompanied by a suppression of tumor growth. Cytotoxic activity against cancer cells was enhanced in probiotic-fed compared to control mice, as evidenced by the elevation of apoptotic markers, such as cleaved caspase 3 and poly (ADP-ribose) polymerase 1 (PARP1), in tumor tissue. Oral administration of Lactobacillus casei induced potent Th1 immune responses and cytotoxic T cell infiltration in the tumor tissue of tumor-bearing mice, resulting in tumor growth inhibition. Thus, the microorganism may hold promise as a novel dietary immunoadjuvant in raising protective anti-cancer immune responses.

scholarly journals BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 817
Author(s):  
Mehreen Ishfaq ◽  
Timothy Pham ◽  
Cooper Beaman ◽  
Pablo Tamayo ◽  
Alice L. Yu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Checkpoint Inhibitors ◽  
No Production ◽  
Free Survival ◽  
T Cell Infiltration ◽  
Car T ◽  
Checkpoint Inhibitor Therapy

MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.

scholarly journals Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 57
Author(s):  
Man-Chin Chen ◽  
Christian Ronquillo Pangilinan ◽  
Che-Hsin Lee
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

scholarly journals Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e73684 ◽  
Author(s):  
Andrew Crowe ◽  
Connie Jackaman ◽  
Katie M. Beddoes ◽  
Belinda Ricciardo ◽  
Delia J. Nelson
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Therapeutic Induction of Tertiary Lymphoid Structures in Cancer Through Stromal Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Johansson-Percival ◽  
Ruth Ganss
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Rejection ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
T Cell Infiltration ◽  
Anti Cancer ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Improving the effectiveness of anti-cancer immunotherapy remains a major clinical challenge. Cytotoxic T cell infiltration is crucial for immune-mediated tumor rejection, however, the suppressive tumor microenvironment impedes their recruitment, activation, maturation and function. Nevertheless, solid tumors can harbor specialized lymph node vasculature and immune cell clusters that are organized into tertiary lymphoid structures (TLS). These TLS support naïve T cell infiltration and intratumoral priming. In many human cancers, their presence is a positive prognostic factor, and importantly, predictive for responsiveness to immune checkpoint blockade. Thus, therapeutic induction of TLS is an attractive concept to boost anti-cancer immunotherapy. However, our understanding of how cancer-associated TLS could be initiated is rudimentary. Exciting new reagents which induce TLS in preclinical cancer models provide mechanistic insights into the exquisite stromal orchestration of TLS formation, a process often associated with a more functional or “normalized” tumor vasculature and fueled by LIGHT/LTα/LTβ, TNFα and CC/CXC chemokine signaling. These emerging insights provide innovative opportunities to induce and shape TLS in the tumor microenvironment to improve immunotherapies.

scholarly journals D-MT Prompts the Anti-Tumor Effect of Oxaliplatin by Inhibiting IDO Expression in a Mouse Model of Colon Cancer

2020 ◽  
Author(s):  
Tiesuo Zhao ◽  
Yongxi Zhang ◽  
Wenyan Fan ◽  
Jing Guo ◽  
Weiwei Ren ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cell ◽  
Tumor Growth ◽  
Malignant Tumors ◽  
Cell Infiltration ◽  
Indoleamine Dioxygenase ◽  
Growth And Survival ◽  
Tumor Bearing ◽  
T Cell Infiltration ◽  
Tumor Tissues

Abstract BackgroundColon cancer is one of the most common malignant tumors in the digestive system. Although oxaliplatin, a chemotherapy drug, has been clinically used to treat colon cancer, its therapeutic effect is unsatisfactory. MethodsIn the present work, it has been proved that indoleamine dioxygenase 2,3 (IDO), an immune checkpoint, is a result of tolerance to chemotherapy. Herein, the anti-tumor effect of treatment with oxaliplatin and D-MT, an IDO inhibitor, on the mice was observed by recording the tumor growth and survival of the mice, and detecting T cell infiltration in tumor tissues and the ratios of immune cells in the spleen by corresponding methods. ResultsWe found that the combination of oxaliplatin and D-MT significantly inhibited tumor growth, prolonged the survival of tumor-bearing mice, increased the cell apoptosis. More importantly, the combination treatment increased the ratios of CD4+ T, CD8+ T and NK cells from the spleen in tumor-bearing mice, and prompted T cell infiltration in tumor tissues. ConclusionThis study provided a new therapeutic strategy for colon cancer treatment in the clinic, especially for patients with oxaliplatin resistance.

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