MEMP PhD Thesis Defense (3:00pm): Ashwin Kumar

Targeting B Lymphocytes to Improve Therapeutic Outcomes for Pediatric Medulloblastoma

Brain cancers are the most prevalent and lethal malignant solid tumors in children. The most aggressive brain cancer in children -- medulloblastoma (MB) -- has four subgroups. Among these sub-groups, group 3 (MYC-driven; G3MB) has the worst prognosis, with a median 5-year overall survival (OS) of only 58% in children and an even lower, 45% in infants, with an average age of diagnosis of 2 to 3 years. The 5-year OS decreases to only 20% with MYC amplification in G3MB. As the complexities of the tumor microenvironment (TME) in medulloblastoma have been unveiled, therapies targeting the immune compartment in these brain cancers has garnered interest. However, the role of B cells in the pediatric TME has been minimally explored despite its prevalence in the microenvironment. Here we report that tumor derived placental growth factor reprograms B cells into an immunosuppressive phenotype, and thus supports tumor growth. We further demonstrate that systemic pharmacologic depletion of B cells improves survival of G3MB-bearing mice by increasing CD8 T cell penetration, activation, and function. These B cells promote immunosuppression in the TME by inhibiting cytotoxic T cell infiltration and function in an IL-10 dependent manner. Finally, we show that systemic B cell depletion can improve the outcome of standard of care doses of radiation therapy as well as lower doses of radiation. Since the standard of care radiation doses can lead to neurotoxicity, our findings suggest that systemic B cell depletion is an effective and safe treatment in combination with lower radiation doses. Since drugs for B cell depletion have been approved for pediatric malignancies, our findings have the potential for rapid translation to the clinic for this devastating disease.

Thesis Supervisor:
Rakesh K. Jain, PhD
A.W. Cook Professor of Radiation Oncology (Tumor Biology), HMS

Thesis Committee Chair:
Alan J. Grodzinsky, ScD
Professor Emeritus of Biological Engineering, Electrical Engineering, and Mechanical Engineering, MIT 

Thesis Readers:
Shiv S. Pillai, MD, PhD
Professor of Medicine and Health Sciences and Technology, MGH and HMS

Mario Suva, MD, PhD
Associate Professor of Pathology, MGH and HMS
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Zoom invitation – 

Ashwin Srinivasan Kumar is inviting you to a scheduled Zoom meeting.

Topic: Ashwin Srinivasan Kumar MEMP PhD Thesis Defense
Time: Friday, April 26, 2024, 3:00 PM Eastern Time (US and Canada)

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