Project 2 will investigate the role of immune responses in dictating the course of BRAF mutant melanoma and how such knowledge can be exploited to develop effective combination therapeutic regimen(s) based on synergy between immunomodulatory molecules and drugs targeting oncogenic BRAF. Expression of immunoregulatory molecules associated with responsiveness and resistance to BRAF-targeted therapy in human and murine melanoma will be determined using molecular, immunohistologic and flow cytometry approaches. Because of the recent therapeutic promise of anti-CTLA-4 therapy in melanoma. Project 2 also will analyze how ahti-CTLA-4 therapy alters the tumor microenvironment in samples from patients with melanoma treated with this immune checkpoint modulator. Functional and clinical validation studies of immunomodulatory targets in BRAF-mutant melanoma initially will determine how BRAF-targeted therapy impacts anti-tumor immunity using human PBMCs and TILs from treated patients and IBIP mice in the settings of responsiveness and resistance to BRAF therapy. Further studies will explore the impact of blocking immunomodulatory targets individually and in combination therapeutic strategies with BRAF-targeted therapy on tumor regression and anti-tumor immunity. Initial functional studies will focus on the CTLA-4 and PD-1/PDL pathways because of their potent immunomodulatory effects in melanoma. This detailed characterization of the immune response in BRAF mutant human and mouse melanomas during tumor growth, treatment and resistance will provide molecular insights into the immune components of BRAF-targeted therapy and guide development of rational combinations of BRAF-targeted therapy and immunotherapy to minimize resistance and achieve durable remission.
|Wargo, Jennifer A; Cooper, Zachary A; Flaherty, Keith T (2014) Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov 4:1377-86|
|Smith, Michael P; Sanchez-Laorden, Berta; O'Brien, Kate et al. (2014) The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNF?. Cancer Discov 4:1214-29|
|Cooper, Zachary A; Juneja, Vikram R; Sage, Peter T et al. (2014) Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res 2:643-54|
|Shi, Min; Roemer, Margaretha G M; Chapuy, Bjoern et al. (2014) Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol 38:1715-23|
|Sullivan, Ryan J; Lorusso, Patricia M; Flaherty, Keith T (2013) The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: where we have been, are, and will be. Clin Cancer Res 19:5283-91|
|Frederick, Dennie T; Piris, Adriano; Cogdill, Alexandria P et al. (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 19:1225-31|
|Chen, Benjamin J; Chapuy, Bjoern; Ouyang, Jing et al. (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 19:3462-73|