Thursday, November 21, 2024
11/21/2024
Project Summary/Abstract Myeloid-derived suppressor cells (MDSCs) exert potent immunosuppressive functions within tumor microenvironments to promote tumor growth. It is critical to investigate the factors that can upregulate the functions of MDSCs because such studies can potentially lead to new treatment strategies to suppress the functions of MDSCs and reactivate the body's immune response to combat cancer. My published data generated from several tumor mouse models strongly support that secretory IgM (sIgM) produced by normal and leukemic B cells has strong immunosuppressive functions in inducing the accumulation and upregulating the functions of MDSCs. To be able to translate my results into a potential therapeutic strategy, I decided to target the synthesis of sIgM by deleting the function of XBP-1s, because the synthesis of sIgM is tightly regulated by a mechanism called regulated IRE-1-dependent decay (RIDD), which is hyperactivated in B cells as a response to deficiency of XBP-1s. Indeed, specific deletion of the XBP-1 gene in leukemic B cells and pharmacological inhibition of XBP-1s in a B cell leukemia mouse model can lead to downregulated immunosuppressive functions of MDSCs, supporting the therapeutic potential of targeting XBP-1s in inhibiting MDSCs. These data prompt me to identify and characterize the mechanisms by which sIgM activates the immunosuppressive functions of MDSCs and to investigate how to target sIgM to control MDSCs. My goals are summarized in the following Specific Aims: (1) to identify and characterize the responsible receptors which mediate the immunosuppressive functions of sIgM; (2) to investigate the downstream molecules that upregulate the immunosuppressive functions of MDSCs upon stimulation by sIgM; and (3) to test whether deleting the function of XBP-1s from B cells can lead to reduced growth of solid tumors via suppressing the production of sIgM. Another main objective of this proposal is to help me initiate and maintain a successful independent research group to conduct high quality research. To ensure successful completion of this objective, I have identified two major areas that I will fortify: (1) to enhance my scientific progress through obtaining guidance from my advisory committee/consultants/collaborators and attending scientific meetings; and (2) to facilitate my career development through participating in workshops to improve my skills in grant writing, manuscript preparation, oral presentation, and laboratory management. With protected time and stability provided by the K22 award, I am confident that I can initiate my own independent research group and successfully compete for R01 funding. My short-term goals are (1) to secure an independent faculty position; (2) to identify molecular mechanisms that mediate immunosuppressive functions of sIgM; and (3) to establish new and close collaborations with colleagues in my future institute. My long-term goals are (1) to develop ongoing projects based on new results obtained; (2) to obtain independent research grant support (R01); (3) to translate my results into potential new therapies; (4) to train graduate students and postdoctoral fellows; and (5) to maintain a successful research program.
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