Clinical significance of humoral immunity against XAGE1 cancer-testis antigen in lung adenocarcinoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 162-162 ◽  
Author(s):  
Mikio Oka ◽  
Koji Kurose ◽  
Midori Isobe ◽  
Minoru Fukuda ◽  
Yoshihiro Ohue
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Antibody Response ◽  
Lung Adenocarcinoma ◽  
Clinical Significance ◽  
Immune Checkpoint ◽  
Expression Profiles ◽  
Immune Checkpoint Molecules ◽  
Advanced Stages ◽  
Cancer Testis

162 Background: Cancer-testis antigens (CTAs) are expressed predominantly in the testis and various types of cancer. Some of CTAs are highly immunogenic and attractive targets for cancer immunotherapy. We identified XAGE1 as a dominant CTA in lung adenocarcinoma (LAD). In this study, we examined immune responses to XAGE1 and the clinical significance in LAD patients. Methods: Expression of XAGE1 and immune checkpoint molecules in LAD tissues was determined by immunohistochemistry. The XAGE1 antibody and T cell immune responses were analyzed in blood samples. Then, overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1 antibody-positive and -negative patients was analyzed. Results: The XAGE1 antigen was expressed in approximately 40% of LAD, and the expression reflected shortened OS of pStage I-IIIA LAD in two japanese cohorts. In addition, expression profiles of XAGE1 and immune checkpoint molecules of PD-L1 and galectin-9 on tumor cells efficiently predicted OS of pStage I-IIIA LAD patients. The XAGE1 antibody response was observed in 6% (9/155) of our pStage I-IIIA, and 20% (34/167) of cStage IIIB-IV LAD, respectively, showing a higher antibody response rate in more advanced stages. In the antibody-positive patients, CD4 and CD8 T cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, the OS of antibody-positive patients significantly prolonged as compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs 15.6 months, P = 0.05) or EGFRmt (34.7 vs 11.1 months, P = 0.001) LAD. Multivariate analysis showed that the XAGE1 antigen expression was a worse predictor in EGFRmt LAD (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in XAGE1 antigen positive LAD (HR: 0.18) and in either EGFRwt or EGFRmt LAD. Conclusions: The XAGE1 antigen induced strong immune responses in LAD patients with more advanced stages, and the production of XAGE1 antibody in these patients showed good prognosis. Our results indicate that the XAGE1 immunity is probably a good prognostic biomarker in LAD and a promising target for immunotherapy of LAD.

scholarly journals MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Lijuan Shao ◽  
Qian He ◽  
Jingbo Wang ◽  
Fei He ◽  
Shengcheng Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoints ◽  
Tumor Cell Migration ◽  
Immune Checkpoint Molecules

AbstractTumor-infiltrating T cells are highly expressive of inhibitory receptor/immune checkpoint molecules that bind to ligand expressed by tumor cells and antigen-presenting cells, and eventually lead to T cell dysfunction. It is a hot topic to restore T cell function by targeting immune checkpoint. In recent years, immunotherapy of blocking immune checkpoint and its receptor, such as PD-L1/PD-1 targeted therapy, has made effective progress, which brings hope for patients with advanced malignant tumor. However, only a few patients benefit from directly targeting these checkpoints or their receptors by small compounds or antibodies. Since the complexity of the regulation of immune checkpoints in tumor cells, further research is needed to identify the novel endogenous regulators of immune checkpoints which can help for developing effective drug target to improve the effect of immunotherapy. Here, we verified that microRNA-326 (miR-326) repressed the gene expression of immune checkpoint molecules PD-L1 and B7-H3 in lung adenocarcinoma (LUAD). We detected that the expression of miR-326 in LUAD tissue was negatively correlated with PD-L1/B7-H3. The repression of PD-L1 and B7-H3 expression through miR-326 overexpression leads to the modification the cytokine profile of CD8+ T cells and decreased migration capability of tumor cells. Meanwhile, the downregulation of miR-326 promoted tumor cell migration. Moreover, blocking PD-L1 and B7-H3 attenuated the tumor-promoting effect induced by miR-326 inhibitor. In tumor-bearing mice, the infiltration of CD8+ T cells was significantly increased and the expression of TNF-α, and IFN-γ was significantly enhanced which contributed to tumor progression after miR-326 overexpression. Collectively, miR-326 restrained tumor progression by downregulating PD-L1 and B7-H3 expression and increasing T cell cytotoxic function in LUAD. Our findings revealed a novel perspective on the complex regulation of immune checkpoint molecules. A new strategy of using miR-326 in tumor immunotherapy is proposed.

scholarly journals Blockage of immune checkpoint molecules increases T‐cell priming potential of dendritic cell vaccine

Immunology ◽  
2019 ◽  
Vol 159 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Hadi Hassannia ◽  
Mitra Ghasemi Chaleshtari ◽  
Fatemeh Atyabi ◽  
Mahshid Nosouhian ◽  
Ali Masjedi ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Immune Checkpoint ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Immune Checkpoint Molecules ◽  
T Cell Priming

Analysis of Spontaneous Vs. Vaccine-Induced Antibody Responses Against Cancer-Testis Antigen MAGE-A3 in Cancer Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5087-5087
Author(s):  
Yanran Cao ◽  
Sacha Gnjatic ◽  
Vincent G. Brichard ◽  
Tim Luetkens ◽  
Sebastian Kobold ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Specific Antibodies ◽  
Fine Specificity ◽  
Specific Memory ◽  
Cancer Testis

Abstract Abstract 5087 Background: Cancer-testis antigens (CTA) are attractive targets for cancer immunotherapy based on their tumor-restricted expression and immunogenicity. A number of CTA, including Melanoma-associated antigen 3 (MAGE-A3), are already under clinical investigation and CTA have been shown to induce strong T cell and humoral immunity in cancer patients receiving active immunotherapy. However, little is known about the fine specificity and the function of vaccine-induced humoral immune responses and it is unclear how they relate to spontaneous CTA-specific immune responses occurring in a minority of patients. Methods: We have performed a longitudinal analysis of spontaneously occurring antibody responses against the CT antigen MAGE-A3 in sera (N=1537), which were collected from patients with multiple myeloma (N=355) over a period of 6 years. Antibody titers were determined by ELISA technique and a B cell ELISPOT assay was applied to estimate the number of MAGEA3-specific memory B cells in peripheral blood of the patients. Fine specificity of the antibody responses was examined using overlapping 20mer peptides spanning the whole sequence of MAGE-A3. The given IgG subtype was determined, and the quality of MAGE-A3-specific antibodies was analyzed using western blot as well as affinity assays. Results were compared to those obtained with MAGE-A3-specific antibody responses induced by vaccination with full-length MAGE-A3 protein and adjuvants AS02B or AS15 in patients with non-small cell lung cancer (NSCLC; N=15). Results: Out of 355 myeloma patients 4 (1.1%) evidenced spontaneous antibody responses against MAGE-A3 at least at one point during the course of their disease. Spontaneously occurring anti-MAGE-A3 humoral responses were usually of low titer. In contrast, all of the vaccinated patients showed high-titered and persisting antibody responses which usually appeared around week 6 after the first application of the vaccine. Accordingly, we found high frequencies of vaccine-induced MAGE-A3-specific memory B cells in the peripheral blood of NSCLC patients while they remained undetectable in most myeloma patients. Vaccine-induced antibody responses underwent affinity maturation reaching affinity levels of spontaneous immune responses after repeated cycles of treatment. MAGE-A3-specific antibodies consisted of IgG1 and IgG3>IgG2>IgG4 subtypes in vaccinated patients whereas spontaneously occurring antibodies were mainly of the IgG2 subtype. Spontaneous as well as vaccine-induced IgG antibodies both recognized the natural full-length protein. Analysis of the fine specificity of the antibody responses revealed that vaccine-induced antibodies recognized a much larger number of MAGE-A3 epitopes than spontaneously occurring antibodies. However, both, spontaneous as well as vaccine-induced responses, most frequently and strongly recognized a specific region within the MAGE-A3 protein corresponding to amino acids 51–70. Conclusions This study demonstrates for the first time important qualitative differences between spontaneously occurring and vaccine-induced antibody responses against the MAGE-A3 antigen in cancer patients. While the potential of both types of antibody responses to promote antigen uptake and induction of T cell responses by antigen-presenting cells might differ, they both recognized the same restricted region within the MAGE-A3 protein. The latter finding might be of importance for the design of future immunotherapies targeting MAGE-A3. Disclosures: No relevant conflicts of interest to declare.

Immunization With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor as a Vaccine Adjuvant Elicits Both a Cellular and Humoral Response to Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2653-2659
Author(s):  
Douglas G. McNeel ◽  
Kathy Schiffman ◽  
Mary L. Disis
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Antibody Response ◽  
Vaccine Adjuvant ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Cellular Immune ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine for the generation and propagation of antigen-presenting cells and for priming a cellular immune response. We report here that use of recombinant human GM-CSF (rhGM-CSF), administered as an adjuvant in a peptide-based vaccine trial given monthly by intradermal injection, led to the development of a T-cell and antibody response to rhGM-CSF. An antibody response occurred in the majority of patients (72%). This antibody response was not found to be neutralizing. In addition, by 48-hour delayed type hypersensitivity (DTH) skin testing, 17% of patients were shown to have a cellular immune response to the adjuvant rhGM-CSF alone. Thymidine incorporation assays also showed a peripheral blood T-cell response to rhGM-CSF in at least 17% of the patients. The generation of rhGM-CSF–specific T-cell immune responses, elicited in this fashion, is an important observation because rhGM-CSF is being used as a vaccine adjuvant in various vaccine strategies. rhGM-CSF–specific immune responses may be incorrectly interpreted as antigen-specific immunity, particularly when local DTH responses to vaccination are the primary means of immunologic evaluation. We found no evidence of hematologic or infectious complications as a result of the development of rhGM-CSF–specific immune responses.

Investigating genes and micro-RNAs that may predict clinical benefits of anti-CTLA-4 therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3043-3043
Author(s):  
Jianjun Gao ◽  
Hong Chen ◽  
Derek Ng Tang ◽  
Padmanee Sharma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Modulation ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Rna Isolation ◽  
Complete Response ◽  
Micro Rnas ◽  
Clinical Benefits

3043 Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, ipilimumab, has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Anti-CTLA-4 treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, anti-CTLA-4 significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that anti-CTLA-4 induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Anti-CTLA-4 treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.

A study of genes and microRNAs that may predict clinical responses to anti-CTLA-4 therapy.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 285-285
Author(s):  
Jianjun Gao ◽  
Hong Chen ◽  
Derek Ng Tang ◽  
Padmanee Sharma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Modulation ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Rna Isolation ◽  
Complete Response ◽  
Expression Of Genes ◽  
Pathway Analyses

285 Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, Ipilimumab (BMS), has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of Ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+ T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved Phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of Ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+ T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Ipilimumab treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, Ipilimumab significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that Ipilimumab induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Ipilimumab treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.

Predicting radiation-induced immune trafficking and activation in localized prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 340-340
Author(s):  
Scott Williams ◽  
Simon P. Keam ◽  
Heloise Halse ◽  
Thu Nguyen ◽  
Catherine Mitchell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Expression Profiles ◽  
High Dose ◽  
Cancer Tissue ◽  
Intrinsic Resistance ◽  
Tissue Segmentation ◽  
T Cell Clone

340 Background: Prostate cancer is frequently cured with high-dose rate brachytherapy as a front-line treatment. However, a significant number unfortunately develop intrinsic resistance. Although considered to be an immune-excluded tissue, immune responses are implicated in driving tumour-eradication in prostate cancer. This has not been proven, and yet is used as the rationale for numerous clinical trials combining radiation and immunotherapies. We hypothesise that there is a predictable but differential relationship between radiation and the immune responses in prostate cancer that could be used to fulfil a clinical need - identifying patients that would benefit from immune intervention in conjunction with radiation. Methods: We present here the results of comprehensive immunological profiling of a cohort of world-unique pre- and post-radiation tissues from 24 patients (RadBank cohort). These were assessed using pathological classification, tissue segmentation (cancer/surrounding stroma), multiplex IHC, gene expression profiling, T-cell receptor sequencing, and spatial computational analysis. Results: Our data resolved three classes of prostate cancer tissue based on immune infiltrate level, immune-activation and -checkpoint gene signatures, spatial clustering and T cell clone sequencing: We have begun to resolve clear patient and clinical classifiers based on immune responses to radiation, and identified patients groups likely to benefit from immune therapy alongside radiation. Conclusions: Importantly, these classifications are associated with baseline gene expression profiles that may be used for pre-clinical stratification and more sophisticated treatment paradigms.

scholarly journals High-Affinity Anti-VISTA Antibody Protects against Sepsis by Inhibition of T Lymphocyte Apoptosis and Suppression of the Inflammatory Response

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Tianzhu Tao ◽  
Lulong Bo ◽  
Teng Li ◽  
Longbao Shi ◽  
Hui Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Apoptosis ◽  
Expression Profiles ◽  
Cytokine Expression ◽  
Lymphocyte Apoptosis ◽  
T Cell Apoptosis ◽  
High Affinity

Background. B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. Methods. Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3+ T cell apoptosis and macrophage activation were determined in vitro. Results. VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3+ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. Conclusion. The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

scholarly journals PD-1 Immune Checkpoint Blockade Promotes Therapeutic Cancer Vaccine to Eradicate Lung Cancer

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 317 ◽  
Author(s):  
Pournima Kadam ◽  
Sherven Sharma
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Tumor Lysate ◽  
Therapeutic Cancer Vaccine ◽  
Tumor Eradication

(1) Background: Targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the activation of immune responses against cancer. Therapeutic vaccination, which induces specific immune responses against tumor antigens (Ags), is an attractive option. (2) Methods: Utilizing a K-RasG12Dp53null murine lung cancer model we determined tumor burden, tumor-infiltrating T cell (TIL) cytolysis, immunohistochemistry, flow cytometry, and CD4 and CD8 depletion to evaluate the efficacy of PD-1 blockade combined with CCL21-DC tumor lysate vaccine. (3) Results: Anti-PD-1 plus CCL21-DC tumor lysate vaccine administered to mice bearing established tumors (150 mm3) increased expression of perforin and granzyme B in the tumor microenvironment (TME), increased tumor-infiltrating T cell (TIL) activity, and caused 80% tumor eradication. Mice with treatment-induced tumor eradication developed immunological memory, enabling tumor rejection upon challenge and cancer-recurrence-free survival. The depletion of CD4 or CD8 abrogated the antitumor activity of combined therapy. PD-1 blockade or CCL21-DC tumor lysate vaccine monotherapy reduced tumor burden without tumor eradication. (4) Conclusion: Immune checkpoint blockade promotes the activity of the therapeutic cancer vaccine. PD-1 blockade plus CCL21-DC tumor lysate vaccine therapy could benefit lung cancer patients.

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