Browsing by Subject "Antigens"

Now showing 1 - 10 of 11
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    Efficacy of novel allogeneic cancer cells vaccine to treat colorectal cancer
    (Frontiers Media, 2024-07-24) Alzeeb, George; Tortorelli, Corinne; Taleb, Jaqueline; De Luca, Fanny; Berge, Benoit; Bardet, Chloé; Limagne, Emeric; Brun, Marion; Chalus, Lionel; Pinteur, Benoit; Bravetti, Paul; Gongora, Céline; Apetoh, Lionel; Ghiringhelli, Francois; Medicine, School of Medicine
    Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient's biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.
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    Lunasin alleviates allergic airway inflammation while increases antigen-specific Tregs
    (PLoS, 2015-02-03) Yang, Xiaowei; Zhu, Jingjing; Tung, Chun-Yu; Gardiner, Gail; Wang, Qun; Chang, Hua-Chen; Zhou, Baohua; Department of Pediatrics, IU School of Medicine
    Lunasin is a naturally occurring peptide isolated from soybeans and has been explored in cancer treatment. Lunasin inhibits NF-κB activation and thus pro-inflammatory cytokine and mediator production in macrophages. In this study we demonstrate that lunasin can effectively suppress allergic airway inflammation in two murine models of asthma. In an OVA+Alum sensitization model, intranasal lunasin treatment at the time of OVA challenges significantly reduced total cells counts in bronchoalveolar lavage (BAL) fluid and eosinophilia, peribronchiolar inflammatory infiltration, goblet cell metaplasia and airway IL-4 production. In an OVA+LPS intranasal sensitization model, lunasin treatment either at the time of sensitization or challenge has similar effects in suppress allergic airway inflammation including significantly reduced total cell and eosinophil counts in BAL fluid, inflammatory gene Fizz1 expression in the lung, and IL-4 production by OVA re-stimulated cells from mediastinal lymph nodes. We further show that intranasal instillation of OVA+lunasin significantly increases OVA-specific regulatory T cell (Treg) accumulation in the lung comparing to OVA only treatment. Taken together, our results suggest lunasin as an anti-inflammatory agent can be potentially used in asthma therapy or as an adjuvant to enhance the induction of antigen-specific Tregs and thus boost the efficacy of allergy immunotherapy.
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    Plant cell-made protein antigens for induction of Oral tolerance
    (Elsevier, 2019-11-15) Daniell, Henry; Kulis, Michael; Herzog, Roland W.; Pediatrics, School of Medicine
    The gut associated lymphoid tissue has effective mechanisms in place to maintain tolerance to food antigens. These can be exploited to induce antigen-specific tolerance for the prevention and treatment of autoimmune diseases and severe allergies and to prevent serious immune responses in protein replacement therapies for genetic diseases. An oral tolerance approach for the prevention of peanut allergy in infants proved highly efficacious and advances in treatment of peanut allergy have brought forth an oral immunotherapy drug that is currently awaiting FDA approval. Several other protein antigens made in plant cells are in clinical development. Plant cell-made proteins are protected in the stomach from acids and enzymes after their oral delivery because of bioencapsulation within plant cell wall, but are released to the immune system upon digestion by gut microbes. Utilization of fusion protein technologies facilitates their delivery to the immune system, oral tolerance induction at low antigen doses, resulting in efficient induction of FoxP3+ and latency-associated peptide (LAP)+ regulatory T cells that express immune suppressive cytokines such as IL-10. LAP and IL-10 expression represent potential biomarkers for plant-based oral tolerance. Efficacy studies in hemophilia dogs support clinical development of oral delivery of bioencapsulated antigens to prevent anti-drug antibody formation. Production of clinical grade materials in cGMP facilities, stability of antigens in lyophilized plant cells for several years when stored at ambient temperature, efficacy of oral delivery of human doses in large animal models and lack of toxicity augur well for clinical advancement of this novel drug delivery concept.
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    A role for HSC70 in regulating antigen trafficking and presentation during macronutrient deprivation
    (2015-02) Deffit, Sarah N.; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Bauer, Margaret E.; Yin, Xiao-Ming
    Globally, protein malnutrition remains problematic, adversely affecting several systems including the immune system. Although poorly understood, protein restriction severely disrupts host immunity and responses to infection. Induction of high-affinity, long-lasting immunity depends upon interactions between B and T lymphocytes. B lymphocytes exploit several pathways including endocytosis, macroautophagy, and chaperone-mediated autophagy to capture and deliver antigens to the endosomal network. Within the endosomal network antigens are processed and loaded onto major histocompatibility complex (MHC) class II molecules for display and recognition by T lymphocytes. To examine the effect of macronutrient malnutrition on MHC class II antigen presentation, we grew B lymphocytes in media containing amino acids, sugars and vitamins but lacking serum, which contains several types of macronutrients. Our studies show macronutrient stress amplified macroautophagy, favoring MHC class II presentation of cytoplasmic antigens targeted to autophagosomes. By contrast, macronutrient stress diminished MHC class II presentation of membrane antigens including the B cell receptor (BCR) and cytoplasmic proteins that utilize the chaperone-mediated autophagy pathway. The BCR plays a critical role in MHC class II antigen presentation, as it captures exogenous antigens leading to internalization and degradation within the endosomal network. While intracellular protease activity increased with macronutrient stress, endocytic trafficking and proteolytic turnover of the BCR was impaired. Addition of high molecular mass macronutrients restored endocytosis and antigen presentation, evidence of tightly regulated membrane trafficking dependent on macronutrient status. Cytosolic chaperone HSC70 has been shown to play a role in endocytosis, macroautophagy, chaperone-mediated autophagy and proteolysis by the proteasome, potentially connecting distinct routes of antigen presentation. Here, altering the abundance of HSC70 was sufficient to overcome the inhibitory effects of nutritional stress on BCR trafficking and antigen presentation suggesting macronutrient deprivation alters the availability of HSC70. Together, these results reveal a key role for macronutrient sensing in regulating immune recognition and the importance of HSC70 in modulating distinct membrane trafficking pathways during cellular stress. These results offer a new explanation for impaired immune responses in protein malnourished individuals.