R01CA266342

Therapeutic Targeting MDSC-Mediated Immune Suppression in Cancer - Project Summary

The prominent change in the myeloid compartment in cancer is the expansion of pathologically activated immature myeloid cells with the potent ability to suppress immune responses – myeloid-derived suppressor cells (MDSC).

In tumor-bearing mice, the total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); less abundant (<20%) population of pathologically activated monocytes (M-MDSC); and a small (<5%) population of early myeloid precursors.

In the tumor microenvironment, MDSC are more immunosuppressive than in peripheral lymphoid organs. However, the mechanism of this phenomenon remains rather elusive. The gaps in our knowledge lie in understanding the mechanisms regulating the function of MDSC in tumors and specific requirements for their targeting.

In this proposal, we will test the hypothesis that there are distinct populations of MDSC in tumors. These populations can be defined by specific markers and, most importantly, have different sensitivity to ferroptotic cell death, which determines their functional activity. We will test the concept that targeting ferroptosis in PMN-MDSC in cancer may have functional consequences for immune responses.

The goal of this project is to uncover the mechanisms regulating myeloid cell function in tumors and to develop novel approaches to the regulation of immune responses in cancer. We propose the following specific aims:

(1) To identify the mechanism of ferroptosis-mediated immune suppression induced by PMN-MDSC in tumors; and
(2) To investigate the therapeutic potential of targeting ferroptosis in PMN-MDSC.

The Wistar Institute Of Anatomy And Biology

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Philadelphia, Pennsylvania 191044205 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 373% from $714,368 to $3,382,023.