Intratumoral T Cell Responses to Therapeutic Vaccination and Intracranial Melanoma

Author: ORCID icon orcid.org/0000-0002-4401-0222
Stevens, Aaron, Experimental Pathology - School of Medicine, University of Virginia
Advisor:
Bullock, Timothy, MD-PATH Research, University of Virginia
Abstract:

CD8 T cells are crucial in the fight against cancer. Despite their positive correlation with prognosis, CD8 T cells are known to become dysfunctional in the tumor microenvironment and are typically unable to eradicate tumors without therapeutic intervention. Therefore, it is imperative that we understand the mechanisms underlying intratumoral CD8 T cell exhaustion and find ways to enhance both their numbers and function within tumors.

Cancer vaccines causing the maturation of dendritic cells and subsequent T cell activation show promise in murine models and are being developed for human patients. We vaccinated mice bearing established murine melanoma tumors with agonistic ╬▒CD40, polyI:C, and tumor antigen. Vaccination led to increased intratumoral T cell numbers and delayed tumor growth, yet did not require trafficking of T cells from the periphery. Pre-existing intratumoral T cells exhibited an acute burst in proliferation but became less functional in response to vaccination. However, the increased intratumoral T cell numbers yielded increased numbers of effector T cells per tumor. Together, our data indicate that the existing T cell response and intratumoral dendritic cells play a critical in vaccination efficacy.

Melanoma, lung, and breast cancer commonly metastasize to the brain, and these metastases are detrimental to patient prognosis. We have interrogated the potential for intracranial melanoma to prime tumor specific T cells. Our data suggests that T cell responses to intracranial melanoma are generated locally within the tumor and/or meninges rather than in the cervical lymph nodes. Additionally, we have examined the potential for focused ultrasound disruption of the blood-brain barrier to improve dendritic cell maturation and the T cell response to intracranial melanoma.

Degree:
PHD (Doctor of Philosophy)
Keywords:
CD8 T cell, Vaccination, CD40, TLR3, Melanoma, Brain, Dendritic cell
Language:
English
Issued Date:
2021/04/30