Summary/Abstract:
I am a postdoctoral fellow at Indiana University who has developed a unique set of skills in tumor immunology
and cancer immunotherapy. Throughout my graduate and postdoctoral studies, I established a productive track-
record with seven first/co-first author manuscripts and a total of 18 top-tier peer-reviewed research and review
papers, including: Nature Nanotechnology, ACS Nano, Nature Communications, The Journal of Clinical
Investigation, Cancer Immunology Research and JCI Insight. Furthermore, I am listed as co-inventor on several
patent applications.
Development/Training: My long-term goal is to establish myself as an independent researcher with the focus
on cancer immunotherapy. Throughout the years, my research became unique in the immunotherapy field as I
am bridging multiple disciplines. This unique skill set requires in-depth knowledge in immunology and
immunotherapy as well as solid understanding in bioinformatics, nanotechnology and the biomedical engineering
field. The K99/R00 award will help in achieving my goal, as I will be guided towards becoming an independent
investigator under the guidance of extremely well-established scientists such as Dr. Xiongbin Lu (cancer biology)
and Dr. Sophie Paczesny (immunology and immunotherapy). I will also closely collaborate with Dr. Chi Zhang
(bioinformatics deconvolution) and Dr. Kenneth Dunn (CODEX® Technology and microscopy).
Research: Despite unprecedented clinical tumor regression observed with checkpoint immunotherapy in
colorectal cancer (CRC) patients harboring microsatellite instability high (MSI-H) tumors, a large proportion of
patients receive little to no improvement. Thus, additional checkpoint inhibitors (CPI) in new pathways are
needed; investigation of tumor microenvironment (TME) cell infiltrates and soluble factors will shed light on
possible targets as well as potential pitfalls to such immunotherapies. In this proposal, I will determine the role
of the interleukin-33 (IL-33) and its receptor STimulation 2 (ST2) in CRC immunotherapy. In my JCI Insight
published preliminary data, I established that ST2 expressing tumor associated macrophages (TAMs) hamper
CD8+ T-cell responses. I therefore hypothesize that ST2 expressing TAMs play an essential role in suppressing
antigen-specific T-cell mediated immune responses and that targeting these TAMs could serve as a potential
novel immune checkpoint pathway. Moreover, I will also investigate the role of ST2 on CRC tumor cells and the
contribution of activating the IL-33/ST2 pathway leading to cancer immunotherapy resistance. Finally, I will
assess the translational potential of IL-33/ST2 therapeutic blockade using the IL-33-trap fusion protein to trap
free local and systemic IL-33 or as an alternative approach a ST2 small molecule inhibitor that will block the
functional binding of IL-33 to its ST2 receptor complex, and these agents in combination with other checkpoint
immunotherapy. Support through this award will greatly increase my likelihood to obtain an R01 at an early
career stage.