scholarly journals Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model

Haematologica ◽  
2021 ◽  
Author(s):  
Dina Stroopinsky ◽  
Jessica Liegel ◽  
Manoj Bhasin ◽  
Giulia Cheloni ◽  
Beena Thomas ◽  
...  
Keyword(s):  
T Cell ◽  
Clonal Diversity ◽  
T Cell Response ◽  
Checkpoint Blockade ◽  
Tumor Challenge ◽  
Cell Responses ◽  
Specific Immunity ◽  
Long Term Survivors ◽  
Tumor Specific Immune Response

We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones.

Dendritic Cell Vaccination Induces HCMV Specific T-Cell Responses in Allogeneic Stem Cell Recipients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 475-475
Author(s):  
Ulrich Grigoleit ◽  
Markus Kapp ◽  
Holger Hebart ◽  
Robert Beck ◽  
Gerhard Jahn ◽  
...  
Keyword(s):  
T Cell ◽  
Hcmv Infection ◽  
T Cell Response ◽  
Post Vaccination ◽  
Cell Responses ◽  
Hcmv Disease ◽  
Prophylactic Vaccination ◽  
Antiviral Chemotherapy ◽  
Observation Period

Abstract Human cytomegalovirus (HCMV) infection remains a major and life threatening infectious complication after allogeneic stem cells transplantation (SCT). We performed a Dendritic cell (DC) vaccination trial by utilizing HCMV peptide loaded mature DC to boost HCMV specific T-cell responses which have been demonstrated to be protective against the development of HCMV disease. DCs were pulsed with nonamer peptides from the HCMV proteins pp65 and pp150, restricted by the HLA-class I elements A1,A2,A3,A11,A68 and B7. We enrolled 24 allogeneic SCT recipients, 6 patients received prophylactic vaccination in view of high risk for HCMV disease. 18 patients were vaccinated therapeutically after HCMV reactivation failed to respond to 4 weeks course of antiviral chemotherapy. Our primary objectives were safety and feasibility of DC vaccination after allogeneic SCT. As all patients with active HCMV infections already received antiviral chemotherapy at the time of DC vaccination, viral load was not a suitable efficacy parameter. Thus, evaluation of efficacy as a secondary objective was based on reconstitution of HCMV-specific CTL responses and long term control of HCMV infection. The study protocol was approved by the local ethical committee and all patients gave written informed consent. DC were generated under GMP conditions and displayed typical surface markers of mature DC (CD1a+/CD14−/CD83+). No local or systemic acute side effects occurred during the first week post vaccination. An observation period of 3 months was determined to evaluate long term side effects and control of HCMV infection. Six patients died during this observation period from other causes and one had no follow-up blood samples, so, 17 patients (5 received prophylactic and 12 received therapeutic vaccination) were evaluable. Only one patient developed Graft-Versus-Host-Disease (GVHD) grade III of the skin and gut. Due to a time lag of 2 months between vaccination and the onset of GVHD, a causative relationship seems to be unlikely. Four of the five patients receiving prophylactic vaccination never showed HCMV reactivation. 10 patients from the therapeutic group cleared their HCMV infection after a mean of 50 days post vaccination. Therefore, 15 of the 17 evaluable patients demonstrated control of HCMV infection after DC vaccination. Among these 15 patients, 10 had detectable specific T-cell response against the vaccine peptides after a mean of 23 days post vaccination. Only 2 from these 10 patients developed a further HCMV reactivation after high dose steroid therapy. Our results show that no relevant side effect was observed in this first DC vaccination trial among allogeneic SCT patients. Additionally, DC are able to induce an efficient peptide specific immune response among allogeneic SCT patients which is capable to protect against HCMV reactivation. In the future, further investigations should be performed to evaluate the feasibility of DC vaccination not only against other infectious complications but also against tumour associated antigens to induce specific T-cell response effectively targeting the particular tumour cell.

scholarly journals Virus-Specific CD4+ and CD8+ Cytotoxic T-Cell Responses and Long-Term T-Cell Memory in Individuals Vaccinated against Polio

2005 ◽  
Vol 79 (10) ◽  
pp. 5988-5995 ◽  
Author(s):  
Rahnuma Wahid ◽  
Martin J. Cannon ◽  
Marie Chow
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses

ABSTRACT The presence of poliovirus (PV)-specific CD4+ T cells in individuals vaccinated against polio has been shown, but CD8+ T-cell responses have not been described. Here, we functionally characterize the CD4+ T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8+ T-cell responses in vitro from vaccinees. Both CD4+ T and CD8+ T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway. Furthermore, the T cells also recognize and kill Sabin 1 vaccine-infected targets. The macrophage-stimulated CD4+ T and CD8+ T cells most likely represent memory T cells that persist for long periods in vaccinated individuals. Thus, immunity to PV vaccination involves not only an effective neutralizing antibody titer but also long-term CD4+ and CD8+ cytotoxic T-cell responses.

Immunosuppression Modulates Immune Responses to AAV Capsid in Human Subjects Undergoing Intramuscular Gene Transfer for Lipoprotein Lipase Deficiency

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 822-822 ◽  
Author(s):  
Daniel J Hui ◽  
Federico Mingozzi ◽  
Annemarie Kleefstra ◽  
Janneke M Meulenberg ◽  
Shyrie Edmonson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cell ◽  
Gene Transfer ◽  
Immune Responses ◽  
T Cell Responses ◽  
T Cell Response ◽  
Safety And Efficacy ◽  
Cell Responses ◽  
Ifn Γ

Abstract Administration of adeno-associated viral vectors (AAV) has resulted in long-term therapeutic gene transfer in multiple large animal models of disease, but attempts to translate systemic administration of AAV to humans have been limited in some cases by an immune response to the vector capsid (Nature Med12:342–7, 2006; Nature Med13:419–422, 2007). To overcome this obstacle, we have proposed that a short course of immunosuppression (IS) be administered with vector injection. Here we report the safety and efficacy results of this maneuver in a trial of AAV-1 administered to skeletal muscle. Lipoprotein lipase (LPL) deficiency is a familial disorder in which insufficient levels of LPL enzyme result in the accumulation of triglycerides in plasma. In a clinical study to correct this disorder, an AAV-1 vector encoding the therapeutic transgene LPL was administered to the skeletal muscle of affected individuals. Eight subjects were assigned to two dose cohorts, receiving 1×1011 genome copies (gc)/kg or 3×1011gc/kg. In this study, one subject receiving the high vector dose experienced a transient, asymptomatic increase in the muscle enzyme creatinine phosphokinase beginning 4 weeks after gene transfer, persisting for several weeks. This was associated with capsid-specific CD4+ and CD8+ T cell activation detectable by IFN-γ ELISPOT and intracellular cytokine staining on PBMC. In total, a T cell response to the AAV capsid, but not to the LPL transgene, was detectable in 4/8 subjects. In some of these subjects, T cell responses were detectable in peripheral blood up to 2 years after gene transfer. To prevent potentially harmful immune responses directed to the AAV capsid, a follow up study in LPL deficient subjects was initiated in which a 12-week regimen of mycophenolate mofetil and cyclosporine A was administered orally starting at the time of AAV-1 intramuscular gene transfer. Two additional subjects were administered AAV-1-LPL in the absence of immunosuppression, to compare the safety and efficacy of two different vector production methods. Overall, IS was well tolerated and no adverse events were reported. At a dose of 3×1011 gc/kg, IS effectively blocked T cell responses to capsid, which were undetectable by IFN-γ ELISPOT in 4/4 subjects, even after IS was discontinued. However, at a dose of 1×1012gc/kg, a delayed IFN-γ response to capsid antigen was observed in 3/5 subjects. In two subjects the T cell response was still detectable after IS was discontinued. T cell responses did not correlate with pre-existing antibody titers in any of the subjects, as positivity for antibodies against the AAV capsid was not predictive of ELISPOT results. Antibody analysis revealed that IS did not have any effect on the development of antibodies against AAV-1 capsid, as all subjects developed humoral immunity against capsid, with predominance of IgG1 antibody subclass. None of the subjects receiving IS developed humoral or cellular immunity to the LPL transgene product. In conclusion, the use of IS in the context of AAV-1 gene transfer for LPL deficiency is safe and at least partially effective in blocking T cell responses directed to the capsid antigen. Ongoing long-term evaluation of transgene expression in these subjects will allow further assessment of the effects of IS on efficacy of gene transfer.

scholarly journals Control of Gammaherpesvirus Latency by Latent Antigen-Specific Cd8+ T Cells

2000 ◽  
Vol 192 (7) ◽  
pp. 943-952 ◽  
Author(s):  
Edward J. Usherwood ◽  
Douglas J. Roy ◽  
Kim Ward ◽  
Sherri L. Surman ◽  
Bernadette M. Dutia ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Initial Load ◽  
Latently Infected ◽  
Infected Cells

The contribution of the latent antigen-specific CD8+ T cell response to the control of gammaherpesvirus latency is currently obscure. Some latent antigens induce potent T cell responses, but little is known about their induction or the role they play during the establishment of latency. Here we used the murine gammaherpesvirus system to examine the expression of the latency-associated M2 gene during latency and the induction of the CD8+ T cell response to this protein. M2, in contrast to the M3 latency-associated antigen, was expressed at day 14 after infection but was undetectable during long-term latency. The induction of the M291–99/Kd CD8+ T cell response was B cell dependent, transient, and apparently induced by the rapid increase in latently infected cells around day 14 after intranasal infection. These kinetics were consistent with a role in controlling the initial “burst” of latently infected cells. In support of this hypothesis, adoptive transfer of an M2-specific CD8+ T cell line reduced the initial load of latently infected cells, although not the long-term load. These data represent the first description of a latent antigen-specific immune response in this model, and suggest that vaccination with latent antigens such as M2 may be capable of modulating latent gammaherpesvirus infection.

scholarly journals Combination Lymphoma Immunotherapy Using Checkpoint Blockade and Intratumoral Virus-like Particles Containing CpG TLR9 Agonist

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3023-3023
Author(s):  
Caitlin D Lemke ◽  
Sue E Blackwell ◽  
Arthur M Krieg ◽  
Aliasger Salem ◽  
George J Weiner
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Intratumoral Injection ◽  
T Cell Response ◽  
Checkpoint Blockade ◽  
Tumor Challenge ◽  
Untreated Tumor

Abstract Checkpoint blockade of immune inhibitory pathways is an exciting therapeutic approach for the treatment of a variety of cancers and has become a standard of care for melanoma and other malignancies. Preliminary results suggest anti-PD-1 has modest single agent activity in patients with non-Hodgkin lymphomas, however there remains considerable room for treatment optimization and improvement through the use of unique immunotherapeutic combinations. We explored one such combination of PD-1 checkpoint blockade and CMP-001, a virus-like particle (VLP) containing a novel immunostimulatory CpG oligodeoxynucleotide (ODN) TLR9 agonist. Clinical grade CMP-001 is available and has been evaluated in over 700 subjects in non-cancer trials. In both preclinical and clinical studies, CMP-001 stimulates a strong and prolonged local Th1 cytokine response designed to enhance antigen presentation. Thus, with intratumoral injection, CMP-001 could augment the development of a tumor-specific T cell response that can be maintained by anti-PD-1 therapy. Syngeneic, immunocompetent mice were inoculated on both the left and right flanks subcutaneously with lymphoma (either A20 B cell lymphoma or E.G7-OVA T cell lymphoma). Anti-PD-1, or isotype control, was delivered intraperitoneally (i.p.) starting one week after tumor challenge and continued twice weekly. CMP-001, or saline control, was delivered intratumorally (i.t.) into the tumor on one flank also starting one week after tumor challenge for a total of 3 doses. Tumor growth and survival was followed. This experimental design allowed us to assess the local (treated tumor) and abscopal (untreated tumor) effect of therapy in two different lymphoma models. Intratumoral CMP-001 enhanced survival, and reduced tumor growth of both the treated and untreated tumors in the A20 lymphoma model. Each of these effects was enhanced with the addition of anti-PD-1 therapy (Figure 1). The anti-tumor effect on both the treated and untreated tumor was lost with depletion of either CD4 or CD8+ T cells demonstrating both cell populations contributed to the therapeutic effect. In the E.G7 model, CMP-001 treatment reduced growth of the local tumor - an effect that was modestly enhanced by anti-PD-1 therapy and dependent on CD8+ T cells. There was no significant response to therapy observed in the untreated E.G7 tumor, perhaps due to the rapid growth of the tumor before an abscopal immune response could develop. We conclude the combination of systemic anti-PD-1 and intratumoral injection of CMP-001 can enhance development of a systemic anti-tumor T cell response and is a promising immunotherapy combination worthy of clinical evaluation. A Phase 1b clinical trial of the combination of anti-PD-1 and CMP-001 is underway in advanced melanoma, and a Phase 1 clinical trial of the same combination is planned in lymphoma, based in part on these results. Figure 1 Figure 1. Disclosures Krieg: Checkmate Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Weiner:Checkmate Pharmaceuticals: Consultancy, Research Funding.

Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

2019 ◽  
Vol 17 (5) ◽  
pp. 350-359
Author(s):  
Liliana Acevedo-Saenz ◽  
Federico Perdomo-Celis ◽  
Carlos J. Montoya ◽  
Paula A. Velilla
Keyword(s):  
T Cell ◽  
Reverse Transcriptase ◽  
Cellular Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Cell Responses ◽  
Clade B ◽  
Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

scholarly journals Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 307
Author(s):  
Yong Bok Seo ◽  
You Suk Suh ◽  
Ji In Ryu ◽  
Hwanhee Jang ◽  
Hanseul Oh ◽  
...  
Keyword(s):  
T Cell ◽  
Nonhuman Primates ◽  
Vaccine Candidate ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Viral Loads ◽  
Cell Responses ◽  
Rapid Spread

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322924
Author(s):  
Tuxiong Huang ◽  
Xiang-Yu Tan ◽  
Hui-Si Huang ◽  
Yu-Ting Li ◽  
Bei-Lei Liu ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Tumour Microenvironment ◽  
T Cell Response ◽  
Cell Responses ◽  
Cancer Associated Fibroblast ◽  
Anticancer Immunotherapy ◽  
Novel Therapeutic Strategies

ObjectiveSolid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).DesignAnti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.ResultsA negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

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