Participant: PROMISE AGEP Research Symposium
Jackline Joy Martín Lasola
Department: Molecular Microbiology and Immunology
Institution: University of Maryland Baltimore (UMB)
Interrogating the role of interleukin-1 receptor-associated kinases (IRAKs) in mediating response to immunotherapies for solid tumors
Department of Microbiology and Immunology and the Marlene and Stuart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine
Cancer care in recent years has faced compelling breakthroughs in approaches to patient management with the advent of immunotherapies for cancer. In particular, checkpoint inhibitors such as ipilimumab and nivolumab have been life-changing in a subset of patients with solid tumors that have otherwise been unresponsive to therapy. These therapies work by blocking inhibitory signals sent by the tumor cells and other cells in the tumor microenvironment to allow a sustained antitumor T cell response against the cancer. Interestingly, when evaluating early responses to checkpoint inhibitors two patterns of response arise. In the subset of patients who do respond to checkpoint inhibitor regimens the response is dramatic and sustained (as noted by progression-free and overall survival), while for those who do not respond to checkpoint inhibitor therapy there is no difference in survival from the previous standard of care. This suggests other markers of immunotherapy response that have yet to be identified. Specifically, this study takes a bioinformatics approach to evaluating clinical trials to determine the status of IRAKs in responders and non-responders for checkpoint inhibitor therapy. In doing so, this study aims to evaluate the potential of IRAK status as a predictor of immunotherapy response and as a druggable target to augment current immunotherapy regimens.
Jackline is a native of the San Francisco Bay Area and completed her undergraduate degrees in both International and Area Studies and Molecular and Cell Biology at the University of California Berkeley in 2010. During her time at the University of California Berkeley she conducted research in molecular phylogenetics and evolution while also being a single parent. Following completion of her bachelor’s degree, Jackline moved to Baltimore to earn her Master of Science degree in Biochemistry and Molecular Biology (Reproductive and Cancer Biology) at Johns Hopkins University where she conducted research investigating the role of infection and inflammation in promoting colorectal tumorigenesis. Concurrent to her time as a student at Hopkins, she worked as a Clinical Research Coordinator for the John Hopkins University School of Medicine’s Center for Viral Hepatitis where she worked with underserved populations to improve public health outreach and prophylaxis against hepatitis C virus infection among injection drug users in Baltimore City. This culminated in her matriculation into the University of Maryland School of Medicine Medical Scientist Training Program in 2014 where she is currently pursuing both her MD and PhD degrees. Ultimately, she intends to combine her interests in patient care among underserved populations with basic and translational cancer research to improve health outcomes for those living with cancer.
GENERAL SUMMARY OF GRADUATE RESEARCH
In recent years, the success of immunotherapy has been heralded as a breakthrough in the treatment of cancer, as typified by the stories of checkpoint inhibitors (such as the antibody therapies ipilimumab and nivolumab that “remove the breaks” to allow for immune activation) and chimeric antigen receptor (CAR) T cells that are engineered to specifically target tumor cells. Despite the advances gained with these treatment modalities, the benefits to patients have not been universal. As such, I am interested in investigating the potential of an innate immune signaling pathway (Toll-like receptor signaling) in modulating the tumor microenvironment in hopes of augmenting the therapeutic effects of treatments for solid tumors. Specifically, I am investigating how an endogenous inhibitor of this signaling pathway, interleukin-1 receptor-associated kinase-M (IRAK-M), alters the inflammation state of the tumor microenviroment and how we can augment its activity so as to enhance the effectiveness of T-cell based immunotherapies. To accomplish this, I use a combination of cell culture assays to characterize the molecular changes imparted by IRAK-M and murine orthotopic tumor models to identify cellular changes in the tumor microenviroment. With this work, we hope to both provide new potential avenues for therapeutic intervention in the field of cancer immunotherapy while also gain a better understanding of how innate immune signaling pathways alter the activity of T cells and the other cellular components of the tumor microenvironment.
SELECTED LIST OF PRESENTATIONS AND PUBLICATIONS
- Kaczanowska S, Joseph AM, Guo J, Tsai A, Lasola JJM, Younger K, Zhang Y, Velasco Gonzales C, Davila E. 2017. A synthetic CD8α:MyD88 co-receptor enhances cytotoxic T cell responses to weakly immunogenic and lowly expressed tumor antigen. Cancer Research 77, 7049-7058. DOI: 10.1158/0008-5472.CAN-17-0653.
- Falade-Nwulia O, Mehta SH, Lasola J, Latkin C, Niculescu A, O’Connor C, Chaulk P, Ghanem K, Page KR, Sulkowski MS, Thomas DL. 2016. Public health clinic-based hepatitis C testing and linkage to care in Baltimore. Journal of Viral Hepatitis 23, 366-74. DOI: 10.1111/jvh.12507.
- Falade-Nwulia O, Irvin R, McAdams-Mahmoud A, Mehta SH, Niculescu A, Lasola J, Baker D, Eppel A, Chaulk P, Page KR, Sulkowski M, Thomas D. 2016. Senior Center Based Hepatitis C Screening in Baltimore. Open Forum Infectious Disease 3: ofv217. DOI: 10.1093/ofid/ofv217.
- Lasola JJM, Hodgson A, Sun X, Wan F. 2014. The PARP1/ARTD1-Mediated Poly-ADP-Ribosylation and DNA Damage Repair in B-Cell Diversification. Antibodies 3, 37-55. DOI: 10.3390/antib3010037
- O’Grady PM, Lapoint RT, Bonacum J, Lasola J, Owen E, Wu Y, DeSalle R. 2011. Phylogenetic and ecological relationships of the Hawaiian Drosophila inferred by mitochondrial DNA analysis. Molecular Phylogenetics and Evolution 58, 255-266. DOI: 10.1016/j.ympev.2010.11.022.
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