Browsing by Subject "cancer immunotherapy"

Now showing 1 - 5 of 5
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    Activation of Natural Killer Cell by Lunasin and Cytokine
    (Office of the Vice Chancellor for Research, 2014-04-11) Kyazike, Sharifah; Lewis, David; Tung, Chun-Yu; Han, Ling; Chang, Hua-Chen
    Cancer immunotherapy is one of the emerging therapeutic strategies to harness the immune system to eradicate chemotherapy-resistant cancerous cells. NK cells can recognize and eliminate cancer cells before adaptive immunity is developed. Human NK cells can be divided into 2 major subsets based on their surface expression of CD56. NK cells with CD56 bright populations are major cytokine producers, while NK cells expressing CD56 dim have higher lytic activity. Due to the role of NK cells in cancer surveillance, any approach to enhance their activity may augment cancer treatment. We have recently shown that soypeptide Lunasin is a novel immune modulating agent that, together with cytokines, enhances IFN- γ and Granzyme B expression by NK cells. This synergism augments the natural cytotoxicity of NK cells against various tumors in vitro as well as in the xenograft model. The objective of this study is to evaluate the effects of Lunasin on antibody-dependent cellular cytotoxicity (ADCC) activity of NK cells against Rituximab-coated human B-lymphoma Raji cells. We also evaluated the expression of several markers involved in NK-mediated tumorcidal activity using flow cytometry. Together, these results suggest that Lunasin could enhance the efficacy of NK cell-based immunotherapy for cancer.
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    Identification of human CD4+ T cell populations with distinct antitumor activity
    (American Association for the Advancement of Science, 2020-07-01) Nelson, Michelle H.; Knochelmann, Hannah M.; Bailey, Stefanie R.; Huff, Logan W.; Bowers, Jacob S.; Majchrzak-Kuligowska, Kinga; Wyatt, Megan M.; Rubinstein, Mark P.; Mehrotra, Shikhar; Nishimura, Michael I.; Armeson, Kent E.; Giresi, Paul G.; Zilliox, Michael J.; Broxmeyer, Hal E.; Paulos, Chrystal M.; Microbiology and Immunology, School of Medicine
    How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies.
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    Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression
    (American Society for Clinical Investigation, 2022-12-01) Colligan, Sean H.; Amitrano, Andrea M.; Zollo, Robert A.; Peresie, Jennifer; Kramer, Elliot D.; Morreale, Brian; Barbi, Joseph; Singh, Prashant K.; Yu, Han; Wang, Jianmin; Opyrchal , Mateusz; Sykes, David B.; Nemeth, Michael J.; Abrams, Scott I.; Medicine, School of Medicine
    While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.
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    Mechanisms of Intrinsic Tumor Resistance to Immunotherapy
    (MDPI, 2018-05-02) Rieth, John; Subramanian, Subbaya; Surgery, School of Medicine
    An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt–β-catenin pathway. Current work in immunotherapy continues to identify various tumor resistance mechanisms; future work is needed to develop adjuvant treatments that target those mechanisms, in order to improve the efficacy of immunotherapy and to expand its scope.
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    On the Use of Marker Strategy Design to Detect Predictive Marker Effect in Cancer Immunotherapy and Targeted Therapy
    (Springer, 2020) Han, Yan; Yuan, Ying; Cao, Sha; Li, Muyi; Zang, Yong; Biostatistics, School of Public Health
    The marker strategy design (MSGD) has been proposed to assess and validate predictive markers for targeted therapies and immunotherapies. Under this design, patients are randomized into two strategies: the marker-based strategy, which treats patients based on their marker status, and the non-marker-based strategy, which randomizes patients into treatments independent of their marker status in the same way as in a standard randomized clinical trial. The strategy effect is then tested by comparing the response rate between the two strategies and this strategy effect is commonly used to evaluate the predictive capability of the markers. We show that this commonly used between-strategy test is flawed, which may cause investigators to miss the opportunity to discover important predictive markers or falsely claim an irrelevant marker as predictive. Then, we propose new procedures to improve the power of the MSGD to detect the predictive marker effect. One is based on a binary response endpoint; the second is based on survival endpoints. We conduct simulation studies to compare the performance of the MSGD with the widely used marker-stratified design (MSFD). Numerical studies show that the MSGD and MSFD has comparable performance. Hence, contrary to popular belief that the MSGD is an inferior design compared with the MSFD, we conclude that using the MSGD with the proposed tests is an efficient and ethical way to find predictive markers for targeted therapies.