scholarly journals 10.03 Interleukin-22 regulates anti-tumor immunity in mouse models of lung and breast carcinoma

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A2.1-A2
Author(s):  
D Briukhovetska ◽  
J Suarez-Gosalvez ◽  
M Schübel ◽  
A Markota ◽  
J Jobst ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Tumor Cells ◽  
Mouse Models ◽  
Cancer Progression ◽  
Antitumor Immunity ◽  
Cytotoxic T Cells ◽  
Metastatic Breast ◽  
Interleukin 22 ◽  
Natural Regulation

BackgroundHigh expression of CD155 (poliovirus receptor, PVR) is associated with a poor prognosis of lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) patients. When overexpressed, this molecule inhibits the antitumor function of NK and cytotoxic T cells through binding to its inhibitory co-receptors TIGIT and CD96, and downregulation of stimulatory CD226 (DNAM-1). However, the exact mechanism of CD155 overexpression on the tumor cells remains unclear. Here we demonstrate that interleukin-22 (IL-22), a cytokine known to promote cancer progression, induces upregulation of CD155 on tumor cells in mouse models of breast and lung cancer and may, thus, inhibit antitumor immunity and promote lung metastasis.Materials and MethodsTo study the influence of IL-22 on antitumor immunity, we utilize IL-22-deficient animals in syngeneic mouse models of metastatic breast and lung cancer. For this purpose, we generated tumor cells deficient in IL-22 receptor (IL-22R) or in CD155 and tumor cells, that constantly express CD155 independent of its natural regulation. Here, we determine the incidence of metastasis and antitumor NK and T cell responses in the lung, the primary site of metastasis.ResultsWe demonstrate that murine cancer cells upregulate CD155 surface expression upon treatment with recombinant IL-22, whereas this effect is abolished in the absence of IL-22R. Furthermore, IL-22-deficient animals have a lower metastatic burden in the lung and demonstrate a dramatic increase in IFN-γ production in NK, and, to a lower extent, cytotoxic T cells. Moreover, this effect is reversed when CD155 is expressed on the tumor cells independent of its natural regulation, which enables lung metastases in IL-22 deficient animals. Phenotypically, NK cells in IL-22 knockout mice have a higher expression of co-stimulatory receptor CD226, which is linked to the antitumor potential of these cells.ConclusionsHere we demonstrate a novel pathway of cytokine-mediated cancer progression, where IL-22 is capable of inducing CD155 on the tumor cells and, therefore, promotes an immunosuppressive tumor microenvironment. This highlights the potential of IL-22 as a target for immunotherapy considering the complexity of the CD155-dependent immunoregulatory network.Disclosure InformationD. Briukhovetska: None. J. Suarez-Gosalvez: None. M. Schübel: None. A. Markota: None. J. Jobst: None. J. Dörr: None. F. Märkl: None. M. Schwerdtfeger: None. A. Öner: None. M. Seifert: None. A. Gottschlich: None. S. Endres: None. S. Kobold: None.

Combination of gemcitabine and adoptive cell therapy of autologous anti-tumor CTL induces clinical activities in patients with refractory lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3053-3053
Author(s):  
U. Toh ◽  
T. Fujii ◽  
S. Takamori ◽  
M. Fukunaga ◽  
E. Ogo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Therapy ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Adoptive Cell Therapy ◽  
Autologous Tumor ◽  
Remarkable Change ◽  
Synergistic Enhancement ◽  
Ifn Γ

3053 Background: Cytotoxic T cells selectively kill autologous tumor cells is powerful for adoptive cell therapy of cancer. Gemcitabine (GEM) is able to induce molecular changes in cancer cells that make them to induce an antigen specific CTL response. This study was to evaluate the anti-tumor and the immunological activity using the CTL in combination with GEM. Methods: The 50Gy irradiated autologous tumor cells were cocultured with PBMCs and CTLs was developed with RPMI 1640 and rIL-2 (50 u/ml) for 7–14 days. Nine pts with non small cell lung cancer failed their prior chemotherapy were enrolled this pilot study. GEM regimen [intravenous (iv.) GEM (1000mg/m2) - day 1, 8 and 15 ] was started without CTL administration for 1st cycle. GEM was administered at least 2 cycles with a 1-week interval and combined with iv. CTL therapy (0.9 x 108 - 4.6 x 108 cells/injection + IL-2 0.4 MIU; biweekly for 6 to 12 injections) from 2nd cycle. The mean total administered T cells were reached to 3.9 x 109 - 5.6 x 109. PBMCs were analyzed their surface markers by Flow Cytometry and the cytokine productions of IFN-γ etc. in the serum were measured by ELISA before and after 1st cycle of GEM administration and 3rd cycles of CTL injection. Results: After finishing 2 cycles of GEM and 3 injections of CTL, the ratio of CD4/CD8 in PBMCs increased in 7/9 pts. In contrast, CD3/CD19 decreased in 6/9 pts. The cytokine production of IFN-γ in the serum revealed an increase after treatment, the levels of TGF-β were decreased simultaneously. There was no remarkable change in the levels of NKG2D in the PBMCs and MIG, IP10 in the serum. The clinical response showed PR/SD/PD was 2/5/2. The tumor marker proteins (CEA) were also decreased significantly in 4 of 9 pts. The adverse effects were tolerable with grade <2 fever, nausea and fatigue and no bone marrow suppression was observed. Conclusions: These results suggested the synergistic enhancement of antitumor effect might be induced between CTLs and anti-cancer agent GEM. Marked clinical responses were observed in two pts after the treatment. Thus this chemo-immunotherapy will be applicable for the patients with refractory lung cancer. No significant financial relationships to disclose.

108 MCY-M11, a CAR-PBMC cell product transiently expressing a mesothelin targeted mRNA CAR, exhibits desirable functional and immune phenotype attributed to sustained antitumor immunity in vitro

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A120-A120
Author(s):  
Sashi Kasimsetty ◽  
Himavanth Gatla ◽  
Dhana Chinnasamy
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Memory T Cells ◽  
Cell Populations ◽  
Epitope Spreading ◽  
Antitumor Response ◽  
Cell Product

BackgroundMCY-M11, an anti-mesothelin CAR (Meso-CAR) mRNA transfected PBMC cell product manufactured through <1 day-process is under clinical evaluation for the treatment of advanced ovarian cancer and peritoneal mesothelioma. In this in-vitro study, we characterized the phenotypic and functional status of immune cell populations in MCY-M11 and their possible role in antitumor immunity.MethodsMCY-M11 cell product were generated using unmanipulated healthy donor PBMCs (n=5) by transfection of Meso-CAR mRNA using MaxCyte’s proprietary Flow Electroporation® system. Frozen MCY-M11 cell product was thawed and cultured for 18 hours, then co-cultured with hMSLNneg or hMSLNpos human mesothelioma cell line, MSTO-211H, or stimulated with anti-CD3/anti-CD28 antibodies in vitro for 8 days. Distinct cell populations in MCY-M11 were evaluated for kinetics and duration of CAR expression, differentiation, activation, exhaustion, and their ability to secrete various immunomodulatory molecules during in vitro stimulation. Antigen-specific proliferation and cytotoxicity of MCY-M11 against hMSLNpos tumor cells as well as their ability to mount long-term antitumor immunity through epitope spreading mechanisms were studied.ResultsIndividual cell populations in MCY-M11 exhibited a consistent but transient Meso-CAR expression persisting for about 7 days. Cell subsets in MCY-M11 acquired early signs of activation and differentiation within 18–24 hours post-culture, but only attained full activation and lineage-specific differentiation upon specific response to hMSLNpos tumor cells. hMSLN antigen experienced MCY-M11 retained significant fractions of Naïve and Central Memory T cells and increased percentage of Effector Memory T cells along with increased expression of CD62L, CD27, and chemokine receptors (CCR5, CCR7, and CXCR3). MCY-M11 exhibited strong antigen-specific cytotoxicity against hMSLNpos tumor cells with corresponding increase in activation and proliferation of CD4+ and CD8+ T cell subsets and displayed low or no acquisition of known exhaustion markers. NK cells also exhibited a functionally superior molecular signature exhibiting increased levels of NKG2D, NKp44, NKp46, FAS, and TRAIL. The Monocytes and B cells in MCY-M11 also acquired an activated, differentiated, and mature phenotype, expressing molecules required for antigen presentation (HLA-DR, HLA-ABC, and CD205) and T cell co-stimulation (CD80 and CD86) to mount a strong antitumor response. These phenotypic changes in cell subsets of MCY-M11 transpired with simultaneous secretion of potent immunostimulatory molecules and chemokines facilitating an extended antitumor response through epitope spreading.ConclusionsWe demonstrated that MCY-M11 is a unique cell product possessing a complete built-in immune cellular machinery with favorable phenotype and enhanced functions specialized in mediating an effective and long-term antitumor response.Trial RegistrationNCT03608618

scholarly journals P2.03-37 The Efficiency of Octamer-4 Specific Cytotoxic T Cells Induce By CD40-B Cells in Killing Lung Cancer Stem-Like Cells

2018 ◽  
Vol 13 (10) ◽  
pp. S730
Author(s):  
X. Zhang ◽  
J. Xu ◽  
F. Hu ◽  
H. Wang ◽  
X. Zheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
B Cells ◽  
Cytotoxic T Cells

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer

2021 ◽  
Vol 13 (594) ◽  
pp. eabd1346
Author(s):  
Christopher S. Garris ◽  
Jeffrey L. Wong ◽  
Jeffrey V. Ravetch ◽  
David A. Knorr
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Antitumor Immunity ◽  
Bladder Tumor ◽  
Immune Surveillance ◽  
Disease Recurrence ◽  
Bcg Therapy ◽  
Agonist Antibody

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

scholarly journals Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3044 ◽  
Author(s):  
Peter Kok-Ting Wan ◽  
Michelle Kwan-Yee Siu ◽  
Thomas Ho-Yin Leung ◽  
Xue-Tang Mo ◽  
Karen Kar-Loen Chan ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Antitumor Immunity ◽  
Cytotoxic T Cells ◽  
Early Response ◽  
Downstream Signaling ◽  
Wide Range ◽  
Immunotherapeutic Strategy ◽  
Poor Efficacy

Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models

2019 ◽  
Vol 68 (11) ◽  
pp. 1865-1873 ◽  
Author(s):  
Bjarne Bogen ◽  
Marte Fauskanger ◽  
Ole Audun Haabeth ◽  
Anders Tveita
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mouse Models ◽  
Cd4 T Cells

scholarly journals FOXA1+ regulatory T cells: A novel T cell subset that suppresses antitumor immunity in lung cancer

2019 ◽  
Vol 514 (1) ◽  
pp. 308-315 ◽  
Author(s):  
Jinyan Liang ◽  
Chen Tian ◽  
Yulan Zeng ◽  
Qifan Yang ◽  
Yangyang Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Antitumor Immunity ◽  
Cell Subset ◽  
T Cell Subset

scholarly journals Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa- associated lymphoid tissue localization

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3785-3791 ◽  
Author(s):  
PC de Bruin ◽  
JA Kummer ◽  
P van der Valk ◽  
P van Heerde ◽  
PM Kluin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Lymphoid Tissue ◽  
Cytotoxic T Cells ◽  
Granzyme B ◽  
Clinical Behavior ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Peripheral T Cell Lymphomas

T-cell non-Hodgkin's lymphomas can be considered the neoplastic equivalents of immunologically functional, site-restricted T lymphocytes. Little is known about the occurrence and clinical behavior of T-cell lymphomas that are the neoplastic equivalents of different functional T-cell subsets. Here, we investigated the prevalence, preferential site, immunophenotype, and clinical behavior of the neoplastic equivalents of activated cytotoxic T cells (CTLs) in a group of 140 nodal and extranodal T-cell lymphomas. Activated CTLs were shown immunohistochemically with a monoclonal antibody against granzyme B, a major constituent of the cytotoxic granules of activated T cells. Granzyme B-positive T-cell lymphomas were mainly found in mucosa- associated lymphoid tissue (MALT; nose, 63% of the cases; gastrointestinal tract, 46%; and lung, 33%). Granzyme B-positive cases with primary localization in MALT were more often associated with angioinvasion (P = .005), necrosis (P = .002), and histologic characteristics of celiac disease in adjacent mucosa not involved with lymphoma. Eosinophilia was more often observed in granzyme B-negative cases (P = .03). Most cases belonged to the pleomorphic medium- and large-cell group of the Kiel classification. CD30 expression was more often found in granzyme B-positive lymphomas of MALT (P = .04), whereas CD56 expression was exclusively found in nasal granzyme B-positive lymphomas. Immunophenotypically, most of the cases should be considered as neoplastic equivalents of activated CTLs based on the presence of T- cell markers on tumor cells. In two cases of nasal lymphoma, tumor cells probably were the neoplastic counterparts of natural killer cells. The prognosis of the granzyme B-positive gastrointestinal T-cell lymphomas was poor but did not differ from granzyme B-negative gastrointestinal T-cell lymphomas. This indicates that, in peripheral T- cell lymphomas, site of origin is more important as a prognostic parameter than derivation of activated CTLs.

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