Antitumor effect of a whole tumor cell vaccine expressing human fibroblast activation protein in murine tumor models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14542-e14542
Author(s):  
Meihua Chen ◽  
Jin Yi Lang ◽  
Tao Li ◽  
Qifeng Wang ◽  
Guangchao Xu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cancer Vaccines ◽  
Neutralizing Antibodies ◽  
Fibroblast Activation Protein ◽  
Cell Vaccine ◽  
Inhibit Tumor Growth ◽  
Tumor Cell Vaccine

e14542 Background: Immunosuppressive factors in the tumor microenvironment reduce the therapeutic efficacy of cancer vaccines; therefore, dampening the tumor immunosuppressive environment while activating antitumor immunity should be a useful approach for cancer therapy. Cancer-associated fibroblasts (CAFs) are among the most important cellular components of the tumor microenvironment and play an important role in the development and progression of tumors. Fibroblast activation protein α (FAPα) is a type II transmembrane protein specifically expressed by CAFs in most epithelial cancers. Gene sequence homology between human and murine FAPα is 90%. Heterogeneity of genes in the evolution of the formation of such nuances can be utilized to break immune tolerance, enhance immunogenicity, induce tumour cell autoimmune responses and thus inhibit tumor growth. Methods: Tumor cells were transfected with human FAPα plasmids employing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. The potential immune mechanisms were investigated through adoptive immunotherapy and 51Cr release assay. The distributions of the immune cells in the tumor microenvironment were detected by immunohistochemical staining and flow cytometry. Results: Our results shown that whole tumor cell vaccine expressing human FAPα significantly inhibit tumor growth and prolong the survival of tumor bearing mice. This antitumor immune response was involved both of cellular and humoral immune responses. FAPα specific neutralizing antibodies were found in the serum of vaccinated mice and CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD4+ T cells and CD8+ T cells, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Conclusions: These findings suggest that whole tumor cell vaccine expressing human FAPα inhibit tumor growth by producing FAPα specific neutralizing antibodies and CTLs, and targeting tumor cells and CAFs. These observations provide a new strategy for the clinical use of genetically modified tumor cells as cancer vaccines.

A vaccine for photodynamic immunogenic cell death: tumor cell caged by cellular disulfide–thiol exchange for immunotherapy

2021 ◽  
Author(s):  
Ya Wen ◽  
Yiqiong Liu ◽  
Fangfang Guo ◽  
Yi Han ◽  
Qiansai Qiu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Vaccine ◽  
Immunogenic Cell Death ◽  
Tumor Initiation ◽  
Established Tumor ◽  
Thiol Exchange ◽  
Protein Shell

Tumor cells, caged by the protein shell, are mediated to an immunogenic cell death and transformed into a hot cell vaccine. Such vaccine protects 75% pre-immunized mice against tumor initiation and significantly retards the established tumor growth.

scholarly journals TMIC-20. ELIMINATION OF SENESCENT ASTROCYTES IN THE BRAIN TUMOR MICROENVIRONMENT ATTENUATES GLIOBLASTOMA RECURRENCE AFTER RADIOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi251-vi251
Author(s):  
Eliot Fletcher-Sananikone ◽  
Bipasha Mukherjee ◽  
Sandeep Burma
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Glioma Cells ◽  
Cell Types ◽  
Normal Brain ◽  
High Doses

Abstract Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR) yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. During GBM therapy, the surrounding brain tissue is irradiated along with the tumor. IR induces senescence in multiple cell types, and senescent stromal cells are known to promote the growth of neighboring tumor cells by secreting cytokines which create a senescence-associated secretory phenotype (SASP). We hypothesize that IR-induced senescence of normal brain cells in the tumor microenvironment is a powerful driver of GBM recurrence. We intra-cranially irradiated C57BL/6J mice, and found evidence of widespread senescence, with the astrocytic population being highly susceptible. Genomic analyses of irradiated brains revealed an altered transcriptomic profile which included upregulation of CDKN1A (p21), a key enforcer of senescence, and increased expression of SASP proteins including HGF, the ligand for the RTK Met. We orthotopically implanted mock-irradiated or irradiated mice with a limiting number of syngeneic glioma cells. Pre-irradiation of mouse brains resulted in a striking increase in tumor growth and invasion driven by Met activation in the tumor cells. Importantly, irradiated p21-/- mouse brains did not exhibit SASP and failed to promote tumor growth. Irradiated primary astrocytes underwent senescence in vitro and promoted the migration of glioma cells, and this could be attenuated with HGF-neutralizing antibodies or by the Met inhibitor Crizotinib. These findings indicate that SASP factors (like HGF) in the irradiated brain microenvironment could drive GBM recurrence after radiotherapy via the activation of RTKs (like MET) in the tumor cells. Significantly, we found that senolytic drugs can selectively kill senescent astrocytes both in vitro and in vivo resulting in attenuated growth of glioma cells. These results are of great translational significance as they indicate that adjuvant therapy with senolytic drugs might attenuate GBM recurrence after radiotherapy.

scholarly journals Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

2021 ◽  
Vol 22 (17) ◽  
pp. 9121
Author(s):  
De Pradip ◽  
Aske Jennifer ◽  
Dey Nandini
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cross Talk ◽  
Critical Role ◽  
Immune Surveillance ◽  
Endometrial Cancers

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 77-77
Author(s):  
Ganapathy Sriram ◽  
Lauren Milling ◽  
Jung-Kuei Chen ◽  
Wuhbet Abraham ◽  
Darrell J. Irvine ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Cell Vaccine ◽  
Tumor Cell Vaccine ◽  
Ifn Γ

77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.

scholarly journals A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Hongwei Tian ◽  
Gang Shi ◽  
Qin Wang ◽  
Yiming Li ◽  
Qianmei Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Cell ◽  
Cancer Vaccines ◽  
Cell Vaccine ◽  
Tumor Cell Vaccine ◽  
Gm Csf ◽  
Cell Responses

Abstract Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.

scholarly journals A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in adoptive therapy for large and established tumors

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 118-127 ◽  
Author(s):  
Matthew J. Goldstein ◽  
Bindu Varghese ◽  
Joshua D. Brody ◽  
Ranjani Rajapaksa ◽  
Holbrook Kohrt ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cellular Therapy ◽  
Cell Vaccine ◽  
Tumor Cell Vaccine ◽  
Adoptive Cellular Therapy ◽  
Adoptive Therapy ◽  
Cell Immunity ◽  
Antigen Presenting

Abstract We designed a whole tumor cell vaccine by “loading” lymphoma tumor cells with CG-enriched oligodeoxynucleotide (CpG), a ligand for the Toll-like receptor 9 (TLR9). CpG-loaded tumor cells were phagocytosed, delivering both tumor antigen(s) and the immunostimulatory CpG molecule to antigen-presenting cells (APCs). These APCs then expressed increased levels of costimulatory molecules and induced T-cell immunity. TLR9 was required in the APCs but not in the CpG-loaded tumor cell. We demonstrate that T cells induced by this vaccine are effective in adoptive cellular therapy for lymphoma. T cells from vaccinated mice transferred into irradiated, syngeneic recipients protected against subsequent lymphoma challenge and, remarkably, led to regression of large and established tumors. This therapeutic effect could be transferred by CD4+ but not by CD8+ T cells. A CpG-loaded whole-cell vaccination is practical and has strong potential for translation to the clinical setting. It is currently being tested in a clinical trial of adoptive immunotherapy for mantle-cell lymphoma.

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