Malignant melanoma is an aggressive cutaneous malignancy with a median overall survival of 6-9 months (9). Immunotherapies have shown dramatic benefits for a subset of melanoma patients. While this is encouraging, the severe toxicity associated with the use of these therapies and the fact that 60% of patients display resistance to them underscores the need for strategies to improve outcomes in resistant patients. One mechanism by which tumors evade the immune response is by up regulating surface expression of CD47. Upon binding signal regulatory protein alpha (SIRPa) on the cell surface of macrophages, CD47 inhibits tumor cell phagocytosis (1). Reagents that block the interaction between CD47 and SIRPa increase clearance of human blood-derived tumors and improve survival in preclinical models (2, 3). Although highly effective in blood-derived tumors, our preliminary studies show that malignant melanoma displays resistance to this therapy through unknown mechanisms. We hypothesize that increasing the display of eat me signals in combination with CD47 blockade will enhance phagocytosis, increase tumor antigen presentation to tumor- specific cytotoxic T cells, and overcome resistance, leading to significant improvements in anti-tumor immune responses. We will test this hypothesis through three specific aims.
In specific aim 1, we will determine if increasing the level of eat me signals expressed by melanoma tumor cells increases tumor cell phagocytosis in vitro, in the presence or absence of CD47 blockade.
In specific aim 2, we will determine the effects of CD47 blockade on T cell migration in vitro. We will also examine if the up regulation of eat me signals is able to promote anti-tumor T cell activation in vivo in the presence or absence of CD47 blockade.
In specific aim 3, we will confirm that T cells which undergo activation in vivo in response to CD47 blockade and chemotherapy are capable of rejecting tumors in adoptive recipients. Completion of these specific aims will enhance our knowledge of the mechanisms by which melanoma cells resist CD47 blockade and will identify mechanisms to mitigate this resistance. The training plan outlined in this grant is designed to help the applicant develop the skills necessary to become an independent investigator including knowledge of cancer biology and immunology, laboratory management, budgeting, teaching, and grant writing. The technical skills to be learned include transfection of mammalian cells, flow cytometry, transmigration assays, live animal imaging, and intravascular staining. In addition to technical skills, the applicant will learn critical thinking design of hypothesis-driven experiments with clear positive and negative results, and managing negative data.
Malignant melanoma is an aggressive form of cancer with a poor prognosis that has displayed resistance to a type of immunotherapy called CD47 blockade. Understanding how melanoma resists this therapy and developing ways to overcome this resistance will allow us to better understand the biology of melanoma while improving patient responses to therapy.
| Trott, Josephine F; Kim, Jeffrey; Abu Aboud, Omran et al. (2016) Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. Oncotarget 7:66540-66557 |
| Weiskopf, Kipp; Anderson, Katie L; Ito, Daisuke et al. (2016) Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20. Cancer Immunol Res 4:1072-1087 |
| Anderson, Katie L; Modiano, Jaime F (2015) Progress in Adaptive Immunotherapy for Cancer in Companion Animals: Success on the Path to a Cure. Vet Sci 2:363-387 |
