Patients with breast and ovarian cancer generate immune responses to the folate receptor alpha

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20043-20043
Author(s):  
K. L. Knutson ◽  
K. R. Kalli ◽  
C. J. Krco ◽  
K. Goodman ◽  
L. E. Kelemen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Folate Receptor ◽  
T Cell Immunity ◽  
Amino Terminus ◽  
Breast And Ovarian Cancer ◽  
Cell Immunity ◽  
Healthy Donors

20043 Background: Studies have demonstrated that the generation of endogenous immunity to specific tumor antigens is associated with improved prognosis for many cancers. Thus, there has been increased efforts to identify tumor-associated antigens to which there is immunity, as these may be tumor rejection antigens. A candidate antigen is the folate receptor alpha (FRα) which is overexpressed in malignancies, especially breast and ovarian cancer. Prior studies involving ovarian and breast cancer patients have demonstrated the presence of FRα-specific cytotoxic T cells in the tumor-associated lymphocyte population. Methods: Using the RANKPEP CD4 T cell epitope prediction algorithm, we predicted promiscuous immunogenic regions of FRα, and tested for immunity in 30 breast or ovarian cancer patients and 18 healthy volunteer donors in order to attain a better understanding of the levels and extent of the endogenous FRα immune response. Immunity was examined using IFN-γ ELIspot analysis and IgG ELISAs. Results: Fourteen peptides were predicted as potential epitopes to which T cells may respond, seven each from the carboxy- and amino-terminus halves of the protein. Greater than 70% of patients demonstrated T cell immunity to at least one of the fourteen peptides. Patients responded to an average of 3 ± 0.7 peptides while healthy donors responded to only 1 ± 0.5 peptides (p = 0.02). Five peptides were recognized by >25% of patients. Responses to three of these peptides were higher (p > 0.05) in the patients than in healthy donors, suggesting that patients generated immunity upon cancer development. Compared to healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor, suggesting natural epitope spreading (p = 0.03). There was no difference between patients and healthy donors in the immune responses to either non-specific stimuli (p = 0.2) or viral peptides (p = 0.5). Patients had detectable FRα-specific IgG antibody consistent with active FRα-specific helper T cell immunity. Conclusions: These findings demonstrate that the FRα is a target of the immune system in patients with breast or ovarian cancer. Understanding the antigens that are naturally targeted by the immune system may be important for diagnosis, prognosis, and immune-based therapies. No significant financial relationships to disclose.

T-Cell Immunity to the Folate Receptor Alpha Is Prevalent in Women With Breast or Ovarian Cancer

2006 ◽  
Vol 24 (26) ◽  
pp. 4254-4261 ◽  
Author(s):  
Keith L. Knutson ◽  
Christopher J. Krco ◽  
Courtney L. Erskine ◽  
Karin Goodman ◽  
Linda E. Kelemen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune System ◽  
T Cell ◽  
Cancer Patients ◽  
Folate Receptor ◽  
Prediction Algorithm ◽  
Amino Terminus ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Healthy Donors

Purpose Studies have demonstrated that the generation of immunity to tumor antigens is associated with improved prognosis for many cancers. A candidate antigen is the folate receptor alpha (FRα), which is overexpressed in breast and ovarian cancers. Our goal in this study was to attain a better understanding of the extent of endogenous FRα immunity. Methods Using a CD4+ T cell epitope prediction algorithm, we predicted promiscuous epitopes of FRα, and tested for immunity in 30 breast (n = 17) or ovarian (n = 13) cancer patients and 18 healthy donors using enzyme-linked immunospot analysis. Results Fourteen peptides were predicted, seven each from the carboxy- and amino-terminus halves of the protein. More than 70% of patients demonstrated immunity to at least one FRα peptide. Patients responded to an average of 3 ± 0.5 peptides, whereas healthy donors responded to 1 ± 0.4 peptides (P = .004). Five peptides were recognized by more than 25% of patients. Responses to three peptides were higher (P < .05) in patients than in healthy donors, suggesting augmented immunity. Compared with healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor (P = .03). There was no difference between each group in the responses to nonspecific (P = .2) and viral stimuli (P = .5). Lastly, patients demonstrated elevated levels of FRα antibodies consistent with a coordinated immune response. Conclusion These findings demonstrate that the FRα is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.

scholarly journals P04.06 mucosal immunization with a cDC1-targeted CTA1 adjuvant vaccine confers protection against melanoma metastasis

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A39.1-A39
Author(s):  
M Arabpour ◽  
S Paul ◽  
R Kiffin ◽  
HG Wiktorin ◽  
K Hellstrand ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Pulmonary Metastases ◽  
T Cell Immunity ◽  
Metastasis Formation ◽  
Mhc I ◽  
Mhc Ii ◽  
Cell Immunity

BackgroundSpecific targeting of anti-cancer vaccines to dendritic cells (DCs) has been shown to mount efficient immune responses against tumor cells. Classical CD103+dendritic cells (also called cDC1) have an inherent ability to cross-present antigens to CD8+ cytotoxic T cells. Here we have explored an anti-tumor vaccine that specifically targets cDC1 cells for protection against and elimination of metastatic melanoma. The vaccine contains the cholera toxin A1 subunit (CTA1) adjuvant and is targeted to cDC1 cells through an anti-CD103 single chain antibody (CD103 scFv).Material and MethodsC57BL/6 mice were injected with wild type or ovalbumin (OVA) expressing B16 melanoma cells either subcutaneously (s.c.) to establish solid tumors, or intravenously (i.v.) to allow the formation of pulmonary metastases. Before or after establishment of tumors, mice were intra-nasally inoculated with a vaccine composed of a CD103 scFv element fused to the adjuvant CTA1 and the MHC I H2kd-restricted OVA epitope SIINFEKL together with the MHC II H2kd-restricted OVA epitope p323 or just the p323 peptide alone (i.e. CTA1-SIINFEKL-p323-CD103 and CTA1-p323-CD103, respectively). Control mice were inoculated with PBS. The growth of solid tumors was carefully monitored and the development of pulmonary metastases was determined 2–3 weeks after tumor cell injection. In addition, antigen-specific T cell immunity following intranasal immunization was evaluated.ResultsTargeting MHC I and MHC II tumor cell epitopes to cDC1, via CD103 ScFv, in conjunction with the CTA1 adjuvant elicited strong tumor specific and protective CD8+ T cell responses as well as CD4+ T cell immunity. Immunization with the CTA1-SIINFEKL-p323-CD103 vaccine significantly reduced the growth of established solid B16F1-OVA melanomas (P<0.001) and potently prevented metastasis formation (P<0.01). Control immunizations with the CTA1-p323-CD103 vaccine tended to reduce metastasis, but tumor-specific CD8+ T cells were required for full therapeutic protection.ConclusionTargeting tumor specific CD8+ T cell epitopes to cDC1, in the context of a powerful adjuvant such as CTA1, leads to the development of efficient anti-tumor immune responses. Our results point towards the utility of cDC1-targeted vaccines in the treatment of established tumors or as a means to prevent metastasis formation.Disclosure InformationM. Arabpour: None. S. Paul: None. R. Kiffin: None. H.G. Wiktorin: None. K. Hellstrand: None. N. Lycke: None. A. Martner: None.

scholarly journals Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Danielle Minns ◽  
Katie Jane Smith ◽  
Emily Gwyer Findlay
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
T Cell Immunity ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Cell Immunity

Neutrophils are the most abundant leukocytes in peripheral blood and respond rapidly to danger, infiltrating tissues within minutes of infectious or sterile injury. Neutrophils were long thought of as simple killers, but now we recognise them as responsive cells able to adapt to inflammation and orchestrate subsequent events with some sophistication. Here, we discuss how these rapid responders release mediators which influence later adaptive T cell immunity through influences on DC priming and directly on the T cells themselves. We consider how the release of granule contents by neutrophils—through NETosis or degranulation—is one way in which the innate immune system directs the phenotype of the adaptive immune response.

scholarly journals CD4+ T cell immunity against the human papillomavirus-18 E6 transforming protein in healthy donors: identification of promiscuous naturally processed epitopes

2005 ◽  
Vol 35 (3) ◽  
pp. 806-815 ◽  
Author(s):  
Valeria Facchinetti ◽  
Samantha Seresini ◽  
Renato Longhi ◽  
Claudio Garavaglia ◽  
Giulia Casorati ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Healthy Donors ◽  
Human Papillomavirus 18

scholarly journals T Cell Immunity to Bacterial Pathogens: Mechanisms of Immune Control and Bacterial Evasion

2020 ◽  
Vol 21 (17) ◽  
pp. 6144 ◽  
Author(s):  
Freya R. Shepherd ◽  
James E. McLaren
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Bacterial Species ◽  
Immune Defense ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Bacterial Antigens

The human body frequently encounters harmful bacterial pathogens and employs immune defense mechanisms designed to counteract such pathogenic assault. In the adaptive immune system, major histocompatibility complex (MHC)-restricted αβ T cells, along with unconventional αβ or γδ T cells, respond to bacterial antigens to orchestrate persisting protective immune responses and generate immunological memory. Research in the past ten years accelerated our knowledge of how T cells recognize bacterial antigens and how many bacterial species have evolved mechanisms to evade host antimicrobial immune responses. Such escape mechanisms act to corrupt the crosstalk between innate and adaptive immunity, potentially tipping the balance of host immune responses toward pathological rather than protective. This review examines the latest developments in our knowledge of how T cell immunity responds to bacterial pathogens and evaluates some of the mechanisms that pathogenic bacteria use to evade such T cell immunosurveillance, to promote virulence and survival in the host.

Effect of Dose on Immune Response in Patients Vaccinated With an HER-2/neu Intracellular Domain Protein—Based Vaccine

2004 ◽  
Vol 22 (10) ◽  
pp. 1916-1925 ◽  
Author(s):  
Mary L. Disis ◽  
Kathy Schiffman ◽  
Katherine Guthrie ◽  
Lupe G. Salazar ◽  
Keith L. Knutson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cell ◽  
Vaccine Dose ◽  
T Cell Immunity ◽  
Protein Vaccine ◽  
Intracellular Domain ◽  
Specific Immunity ◽  
Cell Immunity ◽  
Her 2

Purpose To evaluate the safety of an HER-2/neu intracellular domain (ICD) protein vaccine and to estimate whether vaccine dose impacts immunogenicity. Patients and Methods Twenty-nine patients with HER-2/neu—overexpressing breast or ovarian cancer and with no evidence of disease after standard therapy received a low- (25 μg), intermediate- (150 μg), or high-dose (900 μg) HER-2/neu ICD protein vaccine. The vaccine was administered intradermally, monthly for 6 months, with granulocyte-macrophage colony-stimulating factor as an adjuvant. Toxicity and both cellular and humoral HER-2/neu—specific immunity was evaluated. Results The vaccine was well tolerated. The majority of patients (89%) developed HER-2/neu ICD-specific T-cell immunity. The dose of vaccine did not predict the magnitude of the T-cell response. The majority of patients (82%) also developed HER-2/neu—specific immunoglobulin G antibody immunity. Vaccine dose did not predict magnitude or avidity of the HER-2/neu—specific humoral immune response. Time to development of detectable HER-2/neu—specific immunity, however, was significantly earlier for the high- versus low-dose vaccine group (P = .003). Over half the patients retained HER-2/neu—specific T-cell immunity 9 to 12 months after immunizations had ended. Conclusion The HER-2/neu ICD protein vaccine was well tolerated and effective in eliciting HER-2/neu—specific T-cell and antibody immunity in the majority of breast and ovarian cancer patients who completed the vaccine regimen. Although the dose of vaccine did not impact the magnitude of T-cell or antibody immunity elicited, patients receiving the highest dose developed HER-2/neu—specific immunity more rapidly than those who received the lowest dose.

scholarly journals Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhongfang Wang ◽  
Xiaoyun Yang ◽  
Jiaying Zhong ◽  
Yumin Zhou ◽  
Zhiqiang Tang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Immunity ◽  
T Cell Memory ◽  
Cell Memory ◽  
Host Protection ◽  
Proliferation Capacity ◽  
Cell Immunity ◽  
Healthy Donors ◽  
Close Contacts

AbstractT-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4+ and CD8+ T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.

scholarly journals B and T Cell Immunity in Tissues and Across the Ages

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 24
Author(s):  
Jayaum S. Booth ◽  
Franklin R. Toapanta
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Peripheral Blood ◽  
T Cell Immunity ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Cell Immunity ◽  
Blood Specimens

B and T cells are key components of the adaptive immune system and coordinate multiple facets of immunity including responses to infection, vaccines, allergens, and the environment. In humans, B- and T-cell immunity has been determined using primarily peripheral blood specimens. Conversely, human tissues have scarcely been studied but they host multiple adaptive immune cells capable of mounting immune responses to pathogens and participate in tissue homeostasis. Mucosal tissues, such as the intestines and respiratory track, are constantly bombarded by foreign antigens and contain tissue-resident memory T (TRM) cells that exhibit superior protective capacity to pathogens. Also, tissue-resident memory B (BRM) cells have been identified in mice but whether humans have a similar population remains to be confirmed. Moreover, the immune system evolves throughout the lifespan of humans and undergoes multiple changes in its immunobiology. Recent studies have shown that age-related changes in tissues are not necessarily reflected in peripheral blood specimens, highlighting the importance of tissue localization and subset delineation as essential determinants of functional B and T cells at different life stages. This review describes our current knowledge of the main B- and T-cell subsets in peripheral blood and tissues across age groups.

scholarly journals Loss of host tissue transglutaminase boosts antitumor T cell immunity by altering STAT1/STAT3 phosphorylation in ovarian cancer

2021 ◽  
Vol 9 (9) ◽  
pp. e002682
Author(s):  
Livia Elena Sima ◽  
Siqi Chen ◽  
Horacio Cardenas ◽  
Guangyuan Zhao ◽  
Yinu Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Tissue Transglutaminase ◽  
T Cell Immunity ◽  
Cell Populations ◽  
Tumor Bearing ◽  
Cell Immunity ◽  
Stat3 Phosphorylation

BackgroundTissue transglutaminase (TG2), an enzyme overexpressed in cancer cells, promotes metastasis and resistance to chemotherapy. Its distinct effects in cancer versus the host compartments have not been elucidated.MethodsHere, by using a TG2-/- syngeneic ovarian cancer mouse model, we assessed the effects of TG2 deficiency in the host tissues on antitumor immunity and tumor progression. Multicolor flow cytometry was used to phenotype immune cell populations in the peritoneal environment. Cancer cells recovered from malignant ascites were characterized by RNA sequencing, proliferation, and apoptosis assays.ResultsWe observed that host TG2 loss delayed tumor growth and ascites accumulation and caused increased infiltration of CD8+ T cells and decreased numbers of myeloid cells in the peritoneal fluid. Tumor antigen-specific CD8+ T cell cytotoxic responses were enhanced in ascites from TG2-/- versus TG2+/+ mice and CD8+ T cell depletion caused accelerated ascites accumulation in TG2-/- mice. CD8+ T cells from tumor-bearing TG2-/- mice displayed an effector T cell phenotype, differentiated toward effector memory (Tem). Mechanistically, absence of TG2 augmented signals promoting T cell activation, such as increased cytokine-induced STAT1 and attenuated STAT3 phosphorylation in T cells. Additionally, immune-suppressive myeloid cell populations were reduced in the peritoneal milieu of TG2-/- tumor-bearing mice. In response to the more robust immune response caused by loss of TG2, cancer cells growing intraperitoneally exhibited an interferon-γ(IFN-γ) responsive gene signature and underwent apoptosis. In human specimens, stromal, not tumor, TG2 expression correlated indirectly with numbers of tumor-infiltrating lymphocytes.ConclusionsCollectively, our data demonstrate decreased tumor burden, increased activation and effector function of T cells, and loss of immunosuppressive signals in the tumor microenvironment of TG2-/- mice. We propose that TG2 acts as an attenuator of antitumor T cell immunity and is a new immunomodulatory target.

Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity

2017 ◽  
Vol 398 (9) ◽  
pp. 1027-1036 ◽  
Author(s):  
Tracy M. Josephs ◽  
Emma J. Grant ◽  
Stephanie Gras
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune System ◽  
T Cell ◽  
T Cell Immunity ◽  
Complex Class ◽  
Small Peptides ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Cell Immunity

Abstract It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8–10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8+ T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity.

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