scholarly journals CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

2019 ◽  
Author(s):  
Weiling He ◽  
Hui Zhang ◽  
Shuhua Li ◽  
Yongmei Cui ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Sodium Dodecyl ◽  
Antitumor Immune Response ◽  
Patient Derived Xenograft ◽  
Poliovirus Receptor

AbstractLung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.AbbreviationsLUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A479-A479
Author(s):  
Matteo Rossi ◽  
Elodie Belnoue ◽  
Susanna Carboni ◽  
Wilma Besson-Di Berardino ◽  
Erika Riva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Tumor Control ◽  
Therapeutic Vaccination ◽  
Potent Tumor

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 the Anaxa portions 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.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and 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 a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

scholarly journals Nondominant CD8 T Cells Are Active Players in the Vaccine-Induced Antitumor Immune Response

2011 ◽  
Vol 186 (7) ◽  
pp. 3847-3857 ◽  
Author(s):  
Jennifer N. Uram ◽  
Chelsea M. Black ◽  
Emilee Flynn ◽  
Lanqing Huang ◽  
Todd D. Armstrong ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Antitumor Immune Response

scholarly journals Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle

2006 ◽  
Vol 5 (7) ◽  
pp. 1733-1743 ◽  
Author(s):  
Qiang Zhang ◽  
Ximing J. Yang ◽  
Shilajit D. Kundu ◽  
Michael Pins ◽  
Borko Javonovic ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Growth Factor ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Antitumor Immune Response

scholarly journals Frequency determination of breast tumor-reactive CD4 and CD8 T cells in humans: unveiling the antitumor immune response

2019 ◽  
Vol 8 (8) ◽  
pp. 1607674
Author(s):  
Mariana Pereira Pinho ◽  
Thiago Andrade Patente ◽  
Elizabeth Alexandra Flatow ◽  
Federica Sallusto ◽  
José Alexandre Marzagão Barbuto
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Breast Tumor ◽  
Antitumor Immune Response ◽  
Frequency Determination

scholarly journals Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

2021 ◽  
Vol 23 (1) ◽  
pp. 81
Author(s):  
Abdulaziz A. Almotlak ◽  
Mariya Farooqui ◽  
Adam C. Soloff ◽  
Jill M. Siegfried ◽  
Laura P. Stabile
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Activity ◽  
Oncogenic Signaling ◽  
Murine Bone Marrow

High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.

Double positive CD4+CD8+ T cells are part of the adaptive immune response against Candida albicans

2019 ◽  
Vol 80 (12) ◽  
pp. 999-1005 ◽  
Author(s):  
Barbara Misme-Aucouturier ◽  
Adel Touahri ◽  
Marjorie Albassier ◽  
Francine Jotereau ◽  
Patrice Le Pape ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Candida Albicans ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Double Positive ◽  
Adaptive Immune
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