Team Science in Surgical Oncologic Care
Shannon K. Swisher, MD (she/her/hers)
Douglas Murray Postdoctoral Melanoma Surgical Oncology Research Fellow;
General Surgery Resident
Winship Cancer Institute, Emory University School of Medicine
Atlanta, Georgia, United States
Shannon K. Swisher, MD (she/her/hers)
Douglas Murray Postdoctoral Melanoma Surgical Oncology Research Fellow;
General Surgery Resident
Winship Cancer Institute, Emory University School of Medicine
Atlanta, Georgia, United States
Shannon K. Swisher, MD (she/her/hers)
Douglas Murray Postdoctoral Melanoma Surgical Oncology Research Fellow;
General Surgery Resident
Winship Cancer Institute, Emory University School of Medicine
Atlanta, Georgia, United States
Megan M. Wyatt, MS
Research Lab Manager, Senior Scientist
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Megen C. Wittling, MSTP
Graduate Student, MD PhD Candidate
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Ayana T. Ruffin, PhD
Postdoctoral Fellow
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Keith A. Delman, MD (he/him/his)
Professor of Surgery, Emory University School of Medicine
Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Gregory B. Lesinski, PhD, MPH
Professor, Co-Director Translational GI Malignancy Program
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
.jpg "Michael C. Lowe, MD, MA photo")
Michael C. Lowe, MD, MA
Associate Professor of Surgery, Disease Team Lead and Co-Chair Melanoma Working Group
Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Chrystal M. Paulos, PhD
Associate Professor, Director of Translational Research for Cutaneous Malignancies, PI
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
We identified a novel subset of CD4+ T cells that express high levels of CD26. This CD4+ T cell subset has enhanced stemness and polyfunctionality in vivo. We reported that presence of CD4+ CD26high T cells predicted response to immune checkpoint inhibitor (ICI) Nivolumab and was associated with improved progression-free (PFS) and overall survival (OS). Based on this data, we posit that presence of CD26 on T cells can be leveraged to improve cellular therapies in advanced melanoma.
Methods:
Mouse models expressing a transgenic TCR specific for tyrosinase on melanoma were used for in vivo studies. Mouse TRP-1 CD4+ T cells were sorted by flow cytometry based on CD26 expression: CD26neg or CD26high T cells. B16F10 melanoma-bearing mice were lymphodepleted prior to infusion.
CD26 enzymatic activity was blocked in TRP-1 CD4+ CD26high T cells in vitro using sitagliptin [2mM]. Cells were administered to mice with melanoma and tumor growth was compared to a control group.
Peripheral blood from healthy donors was compared to pts with metastatic melanoma to quantify, phenotype, and characterize the functionality of CD4+ CD26high T cells. Flow cytometry data was analyzed on FlowJo. Statistical analyses were performed using GraphPad Prism.
Results:
Using a TCR-transgenic system where T cells recognized TRP-1 melanoma Ag, we found that CD4+ CD26high T cells elicit potent antitumor activity in vivo compared to mice infused with CD4+ CD26neg T cells (P < 0.05) or no treatment (P < 0.001), Fig 1A.
CD26 enzyme activity was required for improved tumor regression, as administration of sitagliptin impaired antitumor properties of TRP-1 CD4+ CD26high T cells in B16F10 mice with melanoma. At 125 days, 80% of mice that received CD26 enzymatically active cells were alive compared to 10% in the CD26-inhibited group (Fig. 1B).
Pts with metastatic melanoma had fewer CD4+ CD26high T cells than healthy donors (P = 0.001). Among metastatic melanoma pts with fewer CD4+ CD26high T cells at baseline had significantly worse outcomes with decreased PFS (P = 0.014) and OS (P = 0.010), Fig. 1C.
Conclusions:
We discovered that T cells with high CD26 expression effectively can regress solid tumors in vivo, and CD26 enzymatic activity is required to achieve this effect. Degree of CD26 expression accurately predicts response to anti-PD-1 therapy and improves prognostication in advanced melanoma. This supports their utility as a predictive biomarker of response to therapy and individualization of treatment. Ongoing analyses aim to leverage the mechanisms by which these cells enhance the immune response to improve T cell therapy for pts with melanoma.