What We Do

The Sharpe laboratory investigates T cell costimulatory pathways and their immunoregulatory functions. We focus on the roles of these pathways in regulating pathogenic and protective immune responses needed for the induction and maintenance of T cell tolerance and the prevention of autoimmunity, as well as effective antimicrobial and antitumor immunity. We are also involved in studies aimed at translating the fundamental understanding of T cell costimulation into new therapies for autoimmune diseases, chronic viral infections, and cancer. Manipulation of T cell costimulatory pathways is of great therapeutic interest as it may provide a means to enhance immune responses to promote anti-microbial and tumor immunity, or to terminate immune responses to control autoimmune diseases and achieve tolerance for organ transplantation.

Recent Publications

Coinhibitory Pathways in Immunotherapy for Cancer.

Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol. 2016;34 :539-73.Abstract
The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.

T follicular regulatory cells.

Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev. 2016;271 (1) :246-59.Abstract
Pathogen exposure elicits production of high-affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh-mediated B-cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh-mediated B-cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr-cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody-mediated diseases.

Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma.

Cooper ZA, Reuben A, Spencer CN, Prieto PA, Austin-Breneman JL, Jiang H, Haymaker C, Gopalakrishnan V, Tetzlaff MT, Frederick DT, et al. Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma. Oncoimmunology. 2016;5 (3) :e1136044.Abstract
We have made major advances in the treatment of melanoma through the use of targeted therapy and immune checkpoint blockade; however, clinicians are posed with therapeutic dilemmas regarding timing and sequence of therapy. There is a growing appreciation of the impact of antitumor immune responses to these therapies, and we performed studies to test the hypothesis that clinical patterns and immune infiltrates differ at progression on these treatments. We observed rapid clinical progression kinetics in patients on targeted therapy compared to immune checkpoint blockade. To gain insight into possible immune mechanisms behind these differences, we performed deep immune profiling in tumors of patients on therapy. We demonstrated low CD8(+) T-cell infiltrate on targeted therapy and high CD8(+) T-cell infiltrate on immune checkpoint blockade at clinical progression. These data have important implications, and suggest that antitumor immune responses should be assessed when considering therapeutic options for patients with melanoma.

Roles of CD48 in regulating immunity and tolerance.

McArdel SL, Terhorst C, Sharpe AH. Roles of CD48 in regulating immunity and tolerance. Clin Immunol. 2016;164 :10-20.Abstract
CD48, a member of the signaling lymphocyte activation molecule family, participates in adhesion and activation of immune cells. Although constitutively expressed on most hematopoietic cells, CD48 is upregulated on subsets of activated cells. CD48 can have activating roles on T cells, antigen presenting cells and granulocytes, by binding to CD2 or bacterial FimH, and through cell intrinsic effects. Interactions between CD48 and its high affinity ligand CD244 are more complex, with both stimulatory and inhibitory outcomes. CD244:CD48 interactions regulate target cell lysis by NK cells and CTLs, which are important for viral clearance and regulation of effector/memory T cell generation and survival. Here we review roles of CD48 in infection, tolerance, autoimmunity, and allergy, as well as the tools used to investigate this receptor. We discuss stimulatory and regulatory roles for CD48, its potential as a therapeutic target in human disease, and current challenges to investigation of this immunoregulatory receptor.

Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.

Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, et al. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res. 2016;4 (2) :124-35.Abstract
Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124-35. ©2015 AACR.
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Latest News

Congratulations, Frank!

Congratulations, Frank!

May 17, 2016

Congratulations Frank for the publication of your review "Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family" in Immunity.

Congratulations, Peter!

Congratulations, Peter!

May 1, 2016

Congratulations Peter for the publication of your review "T follicular regulatory cells" in Immunological Reviews.

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