scholarly journals P03.02 Protein-based cancer vaccine combined with an oncolytic vaccine promotes potent antitumor immunity

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A13.2-A14
Author(s):  
E Belnoue ◽  
K Das ◽  
M Rossi ◽  
T Hofer ◽  
S Danklmaier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Oncolytic Virus ◽  
Antitumor Immunity ◽  
Checkpoint Blockade ◽  
Tumor Models ◽  
Tumor Associated Antigens ◽  
T Cell Infiltration ◽  
Part Time

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and peptide agonist for Toll like receptor (TLR)-2 and TLR-4 confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models. Oncolytic viruses exert their therapeutic effects by a prolonged oncolytic action and the associated intratumoral inflammation as well as general immune activation. Arming oncolytic virus with tumor associated antigens can additionally enhance the tumor-specific T cell portion and therefore positively affect the balance of antitumor versus antiviral immune responses. The protein vaccine KISIMATM and the recombinant oncolytic virus VSV-GP-TAA (vesicular stomatitis virus pseudotyped with LCMV GP expressing tumor-associated antigens) are both promising vaccine candidates that offer a new cancer vaccination opportunity when combined in heterologous prime-boost regimen.Materials and MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMA-TAA vaccine and/or with intravenous injection of VSV-GP-TAA in different settings. Immunogenicity was assessed by measuring the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in different tumor models. Additionally, transcriptome and immunohistochemistry analyses of the TC-1 tumor have been performed. Combination of heterologous prime-boost with checkpoint blockade PD-1 therapy has been assessed.ResultsPriming with KISIMA-TAA followed by VSV-GP-TAA boost induced a large pool of polyfunctional and persistent antigen-specific cytotoxic T cells in the periphery as well as within the tumor in several tumor models. Frequencies of antigen specific T cells are significantly higher than the respective homologous vaccinations. Additionally, transcriptome analysis of a cold tumor model revealed profound changes in the tumor microenvironment upon heterologous vaccination, including a strong upregulation of gene signatures of several pro-inflammatory cytokines and chemokines required for antitumor immunity along with dendritic and T cell trafficking and activation. This was corroborated by flow-cytometric analysis of tumor-infiltrating leukocytes showing massive CD8+ and CD4+ T cell infiltration as well as repolarization of M2-like macrophages towards M1-phenotype. The presence of the CD8+ T cells within the tumor core was confirmed by immunohistochemistry analysis. Moreover, combining heterologous vaccination with checkpoint blockade further improved its therapeutic efficacy and the number of long-term survivors.ConclusionsThe KISIMA/VSV-GP heterologous prime-boost approach holds great promise for patients with primary or acquired resistance to checkpoint blockade due to its ability to induce tumor-specific T cell, improve T cell infiltration and increase tumor inflammation, even in tumors with limited permissivity for the oncolytic virus.Disclosure InformationE. Belnoue: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. K. Das: None. M. Rossi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. T. Hofer: None. S. Danklmaier: None. T. Nolden: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. L. Schreiber: None. K. Angerer: None. J. Kimpel: None. S. Hoegler: None. L. Kenner: None. D. von Laer: None. K. Elbers: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. G. Wollmann: None. M. Derouazi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA.

scholarly journals Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy

2021 ◽  
Vol 9 (9) ◽  
pp. e003218
Author(s):  
James McAuliffe ◽  
Hok Fung Chan ◽  
Laurine Noblecourt ◽  
Ramiro Andrei Ramirez-Valdez ◽  
Vinnycius Pereira-Almeida ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Models ◽  
Murine Tumor ◽  
T Cell Infiltration

BackgroundThe clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy.MethodsHere, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses.ResultsThe ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells.ConclusionsThese findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.

scholarly journals CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Yutao Wang ◽  
Kexin Yan ◽  
Jiaxing Lin ◽  
Yang Liu ◽  
Jianfeng Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mhc Class I ◽  
Clinical Phenotype ◽  
Angiogenesis Inhibitors ◽  
Class I ◽  
T Cell Infiltration ◽  
Tumor Purity

PurposeTo identify immune-related co-expressed genes that promote CD8+ T cell infiltration in bladder cancer, and to explore the interactions among relevant genes in the tumor microenvironment.MethodWe obtained bladder cancer gene matrix and clinical information data from TCGA, GSE32894 and GSE48075. The “estimate” package was used to calculate tumor purity and immune score. The CIBERSORT algorithm was used to assess CD8+ T cell proportions. Weighted gene co-expression network analysis was used to identify the co-expression modules with CD8+ T cell proportions and bladder tumor purity. Subsequently, we performed correlation analysis among angiogenesis factors, angiogenesis inhibitors, immune inflammatory responses, and CD8+ T cell related genes in tumor microenvironment.ResultsA CD8+ T cell related co-expression network was identified. Eight co-expressed genes (PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, and were enriched in the MHC class I tumor antigen presentation process. The proteins level encoded by these genes (PSMB10, PSMB9, PSMB8, TAP1, IRF1, and FBXO6) were lower in the high clinical grade patients, which suggested the clinical phenotype correlation both in mRNA and protein levels. These factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. PD-1 and PD-L1 positively correlated with these genes which suggested PD-1 expression level positively correlated with the biological process composed by these co-expression genes. In the high expression group of these genes, inflammation and immune response were more intense, and the tumor purity was lower, suggesting that these genes were immune protective factors that improved the prognosis in patients with bladder cancer.ConclusionThese co-expressed genes promote high levels of infiltration of CD8+ T cells in an immunoproteasome process involved in MHC class I molecules. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

scholarly journals P04.05 Modulating tumor microenvironment with arginase-1 specific T cells

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A38.2-A39
Author(s):  
E Martinenaite ◽  
M Aaboe Joergensen ◽  
RE Johansson Mortensen ◽  
S Munir Ahmad ◽  
SE Weis-Banke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Therapeutic Effect ◽  
Potential Role ◽  
Myeloid Cells ◽  
Tumor Site ◽  
Arginase 1 ◽  
Part Time

BackgroundCancer progression is associated with an increased immune suppression at the tumor site. Arginase-1 is an enzyme well-known for its involvement in metabolic immune regulation. At the tumor site, arginase-1 acts by reducing availability of L-arginine to the infiltrating immune cells thus reducing T cell functionality and proliferation. While arginase-1 is expressed by some tumor cells, it has also been shown to be produced by immune inhibitory myeloid cells, such as myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs) and is associated with poor prognosis. Previously, we demonstrated that spontaneous CD4+ and CD8+ T-cell immune responses against arginase-derived, HLA-restricted peptides can be found in both cancer patients and healthy individuals (Martinenaite et al, 2018, DOI: 10.1080/2162402X.2017.1404215). These T cells are present in the memory T cell compartment, and that they are activated in arginase-1 inducing conditions, such as presence of TH2 cytokines IL-4 or IL-13 in vitro (Martinenaite et al, 2019, DOI: 10.1038/s41423-019-0231-3 and DOI: 10.1007/s00262-019-02425-6).Methods and ResultsIn order to explore if arginase-1-specific T cells have a potential role in modulation of immune homeostasis, human arginase-1-specific memory T cells were isolated and expanded for functional characterization. We show that arginase-1-specific T cells specifically recognize arginase-1 expressing cells, such as mRNA transfected autologous dendritic cells (DCs) and B cells as well as M2 polarized macrophages in vitro. In addition, activated arginase-1-specific T cells produce pro-inflammatory cytokines IFNγ and TNFα. Secretion of TH1 cytokines by these T cells suggests potential role as potent immune modulators in the tumor microenvironment, since many arginase-1 expressing myeloid cells are not terminally differentiated and they can be re-polarized to an immunostimulatory, M1-like phenotype. We also observed that targeting of M2-polarized arginase-1 expressing monocytic leukemia cell line THP-1 with arginase-1-specific CD4+ T cells induces upregulation of PD-L1 on the THP-1 cells. Furthermore, we demonstrate that an arginase-1-derive peptide vaccine has a therapeutic effect in syngeneic mouse tumor models (B16 and MC38), both as monotherapy and in combination with anti-PD-1 treatment. The therapeutic effect was associated with increased immune infiltration in the peptide vaccinated mice compared to the control.ConclusionsOur study provides evidence that immune modulatory vaccination targeting arginase-1 is an intriguing way of targeting the immune suppressive microenvironment.Disclosure InformationE. Martinenaite: A. Employment (full or part-time); Significant; IO Biotech. M. Aaboe Joergensen: None. R.E. Johansson Mortensen: None. S. Munir Ahmad: None. S.E. Weis-Banke: None. M. Orebo Holmström: None. A. Wakatsuki Pedersen: A. Employment (full or part-time); Significant; IO Biotech. Ö. Met: None. I.M. Svane: F. Consultant/Advisory Board; Significant; IO Biotech. M. Hald Andersen: A. Employment (full or part-time); Significant; IO Biotech.

scholarly journals SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells

2020 ◽  
Vol 8 (1) ◽  
pp. e000432 ◽  
Author(s):  
Lorena Carmona-Rodríguez ◽  
Diego Martínez-Rey ◽  
Maria Jesús Fernández-Aceñero ◽  
Alicia González-Martín ◽  
Mateo Paz-Cabezas ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Adhesion Molecule ◽  
Cell Infiltration ◽  
Tumor Infiltration ◽  
T Cell Infiltration

BackgroundTumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium.ResultsHere we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell–inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program.ConclusionOur findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically “cold” into “hot” tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type–specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.

scholarly journals 255 Investigating VISTA’s role intrinsic to T cells in the tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A276-A276
Author(s):  
Cassandra Gilmour ◽  
Li Wang ◽  
Juan Dong ◽  
Sarah Stone ◽  
Keman Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Patient Survival ◽  
Cytotoxic T Cells ◽  
Peripheral Tolerance ◽  
Checkpoint Blockade

BackgroundCancer immunotherapies, specifically checkpoint blockade therapies, have demonstrated clinical importance for long term patient survival. One of the major limitations to checkpoint blockade therapies, is the low response rate: ~30% with anti-CTLA4 and anti-PD1 treatment. This may be due to heterogeneity of the patients‘ immune system and the tumor microenvironment including T cell inhibitions. There is a clear need to study this phenomenon and develop additional therapies for long term survival to include a broad range of patients. V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) is a suppressive protein expressed on many cell types in the tumor microenvironment including cytotoxic T cells. VISTA’s role on T cells has been described as maintaining quiescence and peripheral tolerance in a graft vs host disease model, but is not fully understood in context of the tumor microenvironment.MethodsWe use a series of invivo experiments, including T cell specific VISTA knock outs, to understand the role of VISTA on T cells in the tumor microenvironment.ResultsHere we show a series of in vivo experiments that suggest VISTA has a potent intrinsic role on T cells and therefore anti-tumor immunity. Using a T cell specific VISTA knock out, our results suggest that the absence of VISTA on T cells in combination with anti-CTLA4 and vaccine is a very powerful tumor suppressor compared to vaccine and anti-CTLA4 treatment alone. These results also indicate that the absence of VISTA alters the phenotype of cytotoxic T cells in several ways including the production of inflammatory cytokines.ConclusionsOur preliminary data provides foundation to study VISTA’s role intrinsic to T cells in the tumor microenvironment and how disrupting VISTA’s influence intrinsic to T cells may be advantageous for anti-tumor immunity and long term patient survival.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019–2142).

scholarly journals Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments

2020 ◽  
Author(s):  
Kexin Yan ◽  
Yutao Wang ◽  
Ting Xiao
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Interferon Gamma ◽  
Cellular Response ◽  
Antigen Processing ◽  
Gamma Process ◽  
Cell Infiltration ◽  
Melanoma Tumor ◽  
T Cell Infiltration

Abstract Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma, to illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.Method: We obtained melanoma and para-carcinoma tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions and the “estimate” package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the common results in the two cohorts. Results: Nine co-expressed genes (CCL5, GAP5, GZMA, GZMH, IRF1, LAG3, PRF1, NKG7, PSMB10) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, which were enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker, and the tumor purity was higher, suggesting that these genes were immune protective factors that improved the prognosis of melanoma. Besides this, co-expression factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. Conclusion: These nine co-expressed genes promote high levels of infiltration of CD8+ T cells by the cellular response to the interferon−gamma process. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

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