scholarly journals 672 The effect of chemoradiotherapy and tumor histology on the immune contexture of tumor-draining lymph nodes in NSCLC

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A700-A700
Author(s):  
Marieke Fransen ◽  
Famke Schneiders ◽  
Vinitha Kandiah ◽  
Teodora Radonic ◽  
Idris Bahce ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Standard Treatment ◽  
Neoadjuvant Chemoradiotherapy ◽  
Combinatorial Design ◽  
Current Standard ◽  
Tumor Histology ◽  
Immune Contexture ◽  
Draining Lymph Nodes

BackgroundRecently, the concept of locally delivered immune modulatory agents (re-)invigorating sub-optimally primed tumor-specific T cells and lifting suppression in the tumor microenvironment (TME) and tumor-draining lymph nodes (TDLN) has gained attention. TDLN play an important role in the induction of tumor-specific effector T cells. It is here that specialized dendritic cell (DC) subsets present tumor-derived antigens to naïve T cells and start effective adaptive immune responses to cancer. Unfortunately, TDLN are also rapidly targeted by tumors for immune suppression, which may impair the efficacy of immunotherapy. Currently, there is limited knowledge on the immune contexture of TDLN in non-small cell lung cancer (NSCLC), differences between types of tumor histology, and the influence of standard treatment.MethodsIn an exploratory study, we collected and analyzed viable cells from TDLN from patients with NSCLC, scheduled for surgical resection. To date, we have analyzed 43 TDLN from a total of 10 patients with multiparameter flowcytometry panels, either untreated or after neoadjuvant chemoradiotherapy (nCRT).ResultsOur analyses reveal differences between squamous cell carcinoma (SCC) and adenocarcinoma (AC), discernable even within this small cohort. In AC, higher levels of PD-L1 on CD11c+CD1c- LN-resident macrophages and CD1a+ migratory DC were accompanied by a lower activation state of CD8+ T cells by PD-1, CTLA-4 and CD69 expression levels. Furthermore, we found decreased activation of LN-resident DCs (by PD-L1 and CD83 levels) and a striking decrease in PD-1 and CD69 on CD8+ T cells, a decrease in effector and central memory CD8+ T cells, and an increase in naïve CD8+ T cells and Treg subsets after nCRT treatment, the current standard treatment of stage III NSCLC patients.ConclusionsThese AC/SCC –related differences and nCRT-induced alterations in the immune status of hold clues for future patient stratification and combinatorial design of CRT with immunotherapy.Ethics ApprovalThis study was approved by the Medical Ethics Committee; 2017.545

scholarly journals Using Natural Adjuvants to Stimulate Anti-Tumour Immune Responses

2021 ◽  
Author(s):  
◽  
Sabine Kuhn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Site ◽  
Effector Cells ◽  
Draining Lymph Nodes

<p><b>The anti-tumour immune response is often not potent enough to prevent or eradicate disease. Dendritic cells (DCs) are professional antigen-presenting cells that are critical for the initiation of immune responses. While DCs frequently infiltrate tumours, lack of activation together with immuno-suppressive factors from the tumour can hamper an effective anti-tumour immune response.</b></p> <p>In this thesis, the ability of microbial stimuli and danger signals to overcome suppression and re-programme DCs and macrophages to an immuno-stimulatory phenotype was investigated. Whole live Mycobacterium smegmatis and BCG were used to provide multiple pathogen-associated molecular patterns. The intracellularly-recognised toll-like-receptor (TLR) ligands CpG and Poly IC, as well as the extracelullarly recognised TLR ligand LPS, and the danger signal monosodium-urate crystals (MSU) were also included.</p> <p>Bone-marrow derived DCs were found to respond to all adjuvants in vitro and DCs in tumour cell suspensions could be activated ex vivo. To assess the ability of adjuvants to enhance anti-tumour responses in vivo, immune-competent mice bearing established subcutaneous B16F1 melanomas were injected peri-tumorally with the different adjuvants. In line with previous reports, CpG treatment was effective in delaying tumour growth and increasing survival. A similar effect was found with Poly IC, but not with LPS, M. smegmatis, BCG or MSU alone. Combination of M. smegmatis + MSU, however, significantly delayed tumour growth and prolonged survival, while combinations of MSU + BCG or LPS were ineffective. Similar results were obtained using the B16.OVA melanoma and E.G7-OVA thymoma subcutaneous tumour models. In addition, Poly IC and MSU + M. smegmatis reduced primary tumour growth as well as lung metastases in the orthotopic 4T1 breast carcinoma model.</p> <p>Both Poly IC and MSU + M. smegmatis elicited an anti-tumour immune response that required CD8 T cells as well as NK cells. These treatments also resulted in increased proliferation of CD8 T cells and NK cells in tumour-draining lymph nodes, augmented infiltration of effector cells into the tumour, as well as enhanced production of in ammatory cytokines by effector cells and DCs in tumours. In addition, MSU + M. smegmatis also stimulated CD4 T cell proliferation, tumour-infiltrationand activation, while at the same time decreasing the frequency of regulatory T cells in tumours.</p> <p>Activation of a successful immune response to tumours was associated with early induction of IL-12 and IFNʸ, as well as moderate levels of pro-inflammatory cytokines at the tumour site and systemically. Furthermore, anti-tumour activity correlated with the induction of inflammatory monocyte-derived DCs in tumour-draining lymph nodes. These DCs were also observed in adjuvant treated tumours and their appearance was preceded by accumulation of inflammatory monocytes at the tumour site.</p> <p>These findings suggest that specific natural adjuvants can successfully modify the tumour environment and enhance the innate and adaptive anti-tumour immune response to delay tumour progression and increase survival.</p>

scholarly journals Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection

2008 ◽  
Vol 80 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Wânia F. Pereira ◽  
Landi V.C. Guillermo ◽  
Flávia L. Ribeiro-Gomes ◽  
Marcela F. Lopes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Leishmania Major ◽  
Caspase 8 ◽  
Ifn Gamma ◽  
Major Infection ◽  
Draining Lymph Nodes

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following Tcellactivation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells. Treatment with anti-FasLigand, caspase-8 or caspase- 9 inhibitors did not block activation-induced T-cell death. We also investigated whether the blockade of caspase-8 activity would affect the expression of type-1 or type-2 cytokines. At early stages of infection, both CD4 and CD8 T cells expressed IFN-gamma upon activation. Treatment with the caspase-8 inhibitor zIETD-fmk (benzyl-oxycarbonyl-Ile- Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone) reduced the proportion of CD8 T cells and IFN-gamma expression in both CD4 and CD8T cells. We conclude that a non apoptotic role of caspase-8 activity may be required for T cell-mediated type-1 responses during L. major infection.

Sequential Activation of CD8+ T Cells in the Draining Lymph Nodes in Response to Pulmonary Virus Infection

2007 ◽  
Vol 179 (1) ◽  
pp. 391-399 ◽  
Author(s):  
Heesik Yoon ◽  
Kevin L. Legge ◽  
Sun-sang J. Sung ◽  
Thomas J. Braciale
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Sequential Activation ◽  
Draining Lymph Nodes

scholarly journals Combination Immune Treatment of a Highly Aggressive Orthotopic Murine Glioblastoma With Checkpoint Blockade Inhibition and Neoantigen Vaccination

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Connor Liu ◽  
Maximilian Schaettler ◽  
Jay Bowman-Kirigin ◽  
Diane Bender ◽  
Dale K Kobayashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
In Silico Analysis ◽  
Checkpoint Blockade ◽  
Therapeutic Interventions ◽  
Attractive Potential ◽  
Missense Mutations ◽  
Draining Lymph Nodes

Abstract INTRODUCTION The treatment of glioblastoma remains a challenge for modern therapy. Checkpoint blockade inhibitors (CBI), designed to block inhibitory T-cell signaling, represent attractive potential therapeutic interventions. However, glioblastoma response rates to CBI remain low. To this end, preclinical models are critical to studying multi-modal immune interventions to overcome CBI resistance. Therefore, we set out to identify endogenous neoantigens in a CBI resistant murine glioblastoma and assess the efficacy of neoantigen vaccination in combination with CBI treatment. METHODS Whole exome DNA and RNA sequencing was used to identify expressed, missense mutations in the C57BL/6 derived murine glioblastoma, CT2A. The pVAC-seq software suite was used to identify candidate neoantigens predicted to bind H2-Kb and H2-Db molecules. CD8 + T cells isolated from CT2A tumor-infiltrating lymphocytes (TIL) were screened for neoantigen reactivity by IFN-gamma enzyme linked immunospot assays. Survival analysis was performed on intracranial tumor bearing mice treated with neoantigen vaccination, anti-PD-L1, or combination therapy. RESULTS In silico analysis identified 649 CT2A-derived candidate neoantigens predicted to bind H2-Kb or H2-Db molecules. Of the 40 top-ranking neoantigen candidates, 16 elicited CD8 + TIL responses in mice vaccinated with cognate peptides. Assessing for endogenous reactivity, we identified neoantigen specific CD8 + T cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted, Epb4 (H471L) and Pomgnt1 (R497L), and one H2-Db restricted neoantigen, Plin2 (G332R). Survival studies showed that therapeutic neoantigen vaccination with Epb4, Pomgnt1, and Plin2, in combination with anti-PD-L1 treatment was superior to anti-PD-L1 alone. CONCLUSION We identified endogenous neoantigen specific CD8 + T cells within brain tumors and draining lymph nodes of a CBI resistant murine glioblastoma. Furthermore, we find that neoantigen vaccination significantly augments survival benefit in combination with anti-PD-L1 treatment. These observations provide important preclinical correlates for glioblastoma immunotherapy trials and support further investigation into the effects of multi-modal immunotherapeutic interventions on anti-glioma immunity.

scholarly journals Using Natural Adjuvants to Stimulate Anti-Tumour Immune Responses

2021 ◽  
Author(s):  
◽  
Sabine Kuhn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Site ◽  
Effector Cells ◽  
Draining Lymph Nodes

<p><b>The anti-tumour immune response is often not potent enough to prevent or eradicate disease. Dendritic cells (DCs) are professional antigen-presenting cells that are critical for the initiation of immune responses. While DCs frequently infiltrate tumours, lack of activation together with immuno-suppressive factors from the tumour can hamper an effective anti-tumour immune response.</b></p> <p>In this thesis, the ability of microbial stimuli and danger signals to overcome suppression and re-programme DCs and macrophages to an immuno-stimulatory phenotype was investigated. Whole live Mycobacterium smegmatis and BCG were used to provide multiple pathogen-associated molecular patterns. The intracellularly-recognised toll-like-receptor (TLR) ligands CpG and Poly IC, as well as the extracelullarly recognised TLR ligand LPS, and the danger signal monosodium-urate crystals (MSU) were also included.</p> <p>Bone-marrow derived DCs were found to respond to all adjuvants in vitro and DCs in tumour cell suspensions could be activated ex vivo. To assess the ability of adjuvants to enhance anti-tumour responses in vivo, immune-competent mice bearing established subcutaneous B16F1 melanomas were injected peri-tumorally with the different adjuvants. In line with previous reports, CpG treatment was effective in delaying tumour growth and increasing survival. A similar effect was found with Poly IC, but not with LPS, M. smegmatis, BCG or MSU alone. Combination of M. smegmatis + MSU, however, significantly delayed tumour growth and prolonged survival, while combinations of MSU + BCG or LPS were ineffective. Similar results were obtained using the B16.OVA melanoma and E.G7-OVA thymoma subcutaneous tumour models. In addition, Poly IC and MSU + M. smegmatis reduced primary tumour growth as well as lung metastases in the orthotopic 4T1 breast carcinoma model.</p> <p>Both Poly IC and MSU + M. smegmatis elicited an anti-tumour immune response that required CD8 T cells as well as NK cells. These treatments also resulted in increased proliferation of CD8 T cells and NK cells in tumour-draining lymph nodes, augmented infiltration of effector cells into the tumour, as well as enhanced production of in ammatory cytokines by effector cells and DCs in tumours. In addition, MSU + M. smegmatis also stimulated CD4 T cell proliferation, tumour-infiltrationand activation, while at the same time decreasing the frequency of regulatory T cells in tumours.</p> <p>Activation of a successful immune response to tumours was associated with early induction of IL-12 and IFNʸ, as well as moderate levels of pro-inflammatory cytokines at the tumour site and systemically. Furthermore, anti-tumour activity correlated with the induction of inflammatory monocyte-derived DCs in tumour-draining lymph nodes. These DCs were also observed in adjuvant treated tumours and their appearance was preceded by accumulation of inflammatory monocytes at the tumour site.</p> <p>These findings suggest that specific natural adjuvants can successfully modify the tumour environment and enhance the innate and adaptive anti-tumour immune response to delay tumour progression and increase survival.</p>

scholarly journals Heterologous Prime-Boost Vaccination with a Peptide-Based Vaccine and Viral Vector Reshapes Dendritic Cell, CD4+ and CD8+ T Cell Phenotypes to Improve the Antitumor Therapeutic Effect

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6107
Author(s):  
Tamara Hofer ◽  
Matteo Rossi ◽  
Susanna Carboni ◽  
Wilma Di Berardino Besson ◽  
Dorothee von Laer ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Viral Vector ◽  
Mouse Tumor ◽  
Protein Vaccine ◽  
Boost Vaccination ◽  
Draining Lymph Nodes

Heterologous prime-boost settings with a protein vaccine and the viral vector vesicular stomatitis virus, both expressing tumor-associated antigens (KISIMA-TAA and VSV-GP-TAA), have been previously shown to generate potent antitumor immunity. In the cold TC-1 model (HPV antigen) and the immune-infiltrate MC-38 model (Adpgk, Reps1 and Rpl18 neo-antigens), we further investigated pivotal immune cells that educate CD8+ T cells. Heterologous prime-boost vaccination induced a superior antitumor response characterized by the increase in number and functionality of antigen-specific CD8+ T cells, recruitment of cross-presenting dendritic cells, and polarization of CD4+ T cells towards an antitumor Th1 phenotype within the tumor and tumor-draining lymph nodes, turning the cold TC-1 tumor into a hot, inflamed tumor. In the inflamed MC-38 tumor model, treatment combination markedly prolonged the overall survival of mice. Treatment with multi-epitope vaccines also induced high frequencies of multiple antigen specificities in the periphery and in the tumor. Prime-boost treatment reduced tumor-infiltrating regulatory CD4+ T cells whilst increasing cross-presenting dendritic cells in tumor-draining lymph nodes. In conclusion, heterologous prime-boost vaccination possesses the ability to induce a potent anti-tumor response in both immune-excluded and immune-infiltrated mouse tumor models. Additionally, this study highlights the design of a multi-epitope vaccine for cancer immunotherapy.

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