- Johns Hopkins University, Ph.D.
- St. Jude Children's Research Hospital, Postdoc
- Western Michigan University, B.S.
Education & Training
Bold denotes University of Pittsburgh authors.
Peralta RM, Xie B, Lontos K, Nieves-Rosada H, Spahr K, Joshi S, Ford BR, Quann K, Frisch AT, Dean V, Philbin M, Cillo AR, Gingras S, Poholek AC, Kane LP, Rivadeneira DB, and Delgoffe GM. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat Immunol (in press).
DePeaux K, Rivadeneira DB, Lontos K, Dean VG, Gunn WG, Watson MJ, Yao T, Wilfahrt D, Hinck C, Wieteska L, Thorne SH, Hinck AP, and Delgoffe GM. An oncolytic virus delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment. J Exp Med. 2023:220(10). Aug 8.
Vignali PDA, DePeaux K, Watson MJ, Ye C, Ford BR, Lontos K, McGaa NK, Scharping NE, Menk AV, Robson SC, Poholek AC, Rivadeneira DB, and Delgoffe GM. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat Immunol. 2023 Feb;24(2):267-269.
Ford BR*, Vignali PDA*, Rittenhouse NL*, Scharping NE*, Peralta R, Lontos K, Frisch AT, Delgoffe GM^, and Poholek AC. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci Immunol. 2022 Aug 5;7(74).
Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, Peralta RM, Wang Y, Wang Y, DePeaux K, Poholek AC, and Delgoffe GM. “Mitochondrial stress induced by continuous stimulation under hypoxia rapidly promotes a T cell exhaustion.” Nat Immunol. 2021 Jan 4.
Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, Menk AV, Rittenhouse NL, DePeaux K, Whetstone RD, Vignali DAA, Hand TW, Poholek AC, Morrison BM, Rothstein JD, Wendell SG, and Delgoffe GM. “Metabolic support of tumor-infiltrating regulatory T cells by lactic acid.” Nature. 2021 Feb 15.
Rivadeneira DB, DePeaux K, Kulkarni A, Tabib T, Menk AV, Sampath P, Lafyatis R, Ferris RL, Sarkar SN, Thorne SH, and Delgoffe GM. “Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance.” Immunity. 2019 Aug 27.
Najjar YG, Menk AV, Sander C, Rao U, Karunam urthy A, Bhatia R, Zhai S, Kirkwood JM, Delgoffe GM. “Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma.” JCI Insight. 2019 Feb 5. 2019. Mar 7; 4(5).
Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, Watkins SC, Delgoffe GM. 41BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp Med. 2018 Mar 2.
Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, Salvatore S, Bae H, Xie J, Young HA, Wendell SG, and Delgoffe GM. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 2018 Feb 6;22(6):1509-1521.
Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM. “The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction.” Immunity. 2016 Aug 16;45(2):374-88.
Scharping NE*, Menk AV*, Whetstone RD, Zeng X, Delgoffe GM. "Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia." Cancer Immunol Res. 2016 Dec 9.
- immunometabolism
- cancer immunology
- regulatory T cell biology
- exhausted T cell biology
- immunotherapy of cancer
- control of immunity by diet
The Delgoffe Lab studies the metabolic contributions to T cell fate and function. The activation, expansion, and differentiation of T cells requires the interpretation of many complex signals including those from the antigen receptor, costimulatory and coinhibitory molecules, and cytokines. It has now become clear that metabolism represents another key mechanism by which T cells can be regulated. In addition, nutrient sensing and metabolic reprogramming pathways are intrinsically tied to signaling involved in T cell biology. Given that nutrients are limiting in the microenvironment of cancer, our studies have immediate translation as modalities to improve cancer immunotherapy.
Metabolic barriers to effective cancer immunotherapy
Cancer cells, by nature of their unrestrained proliferation, are metabolically deregulated. This results in both a local depletion of nutrients and oxygen but also a build-up of toxic byproducts. This creates an inhospitable environment for infiltrating immune cells, suggesting that tumor cells evade immunity in part by starving tumor-reactive cells. Our lab studies how hypoxia, acidosis, and local nutrient depletion represent barriers to immunotherapies like adoptive cell therapy, costimulatory therapy, oncolytic viruses, and checkpoint blockade. Further, our work has identified pharmacologic modalities by which tumor cell metabolism can be remodeled, leading to improved immunotherapy responses. Some of these modalities are being translated into clinical trials here in Pittsburgh and beyond.
Metabolic underpinnings to T cell exhaustion
T cell exhaustion is a defined functional state in which terminally differentiated T cells become hyporesponsive to their antigen. Persistent antigen in chronic viral infection and in cancer represent key drivers of this phenotype, but it is still unclear how T cell exhaustion is induced and why, precisely, exhausted T cells are dysfunctional. The laboratory has found that exhausted T cells lost functional mitochondria and that this metabolic insufficiency underlies both their differentiation and dysfunction. We utilize cutting edge technology to profile the contributions of metabolic pathways to the avoidance of the exhausted T cell phenotype and explore novel ways to reverse T cell exhaustion to improve therapies.
Regulatory T cell metabolism and its implication in cancer and autoimmunity
Regulatory T cells are vital components of a healthy immune system but become dysfunctional in autoimmunity and hyperactive in cancer. Our laboratory studies how tissue-resident and tumor-resident regulatory T cells meet their metabolic demands, and have found that these cells have unique metabolic profiles that underlie their functional identity. Projects in the lab seek to understand the contribution of these novel metabolic pathways to regulatory T cell function and explore how to exploit these potential metabolic vulnerabilities to combat cancer and autoimmunity.
Oncolytic virus immunotherapy and modalities for therapeutic enhancement
While checkpoint blockade immunotherapy can reinvigorate resident, dormant antitumor immunity, many microenvironments are either immune excluded (in which T cells cannot penetrate the tumor bed) or immune desert (in which T cells are present whatsoever), and represent poor response to checkpoint blockade. Oncolytic viruses are engineered agents which replicate specifically in tumor cells and lead to cancer cell lysis. Further, these viruses stimulate potent, new tumor immunity dominated by T cells. Our lab studies the mechanisms by which oncolytic viruses function to stimulate new immunity and how the virus itself can be employed to deliver metabolic modulatory therapy.
Energetic contributions to T cell activation and motility
Early in our lab’s history we found that T cells make drastic changes to their metabolic program almost immediately upon TCR ligation (within minutes). We hypothesize this is due to immediate metabolic requirements necessary for early T cell function. Our lab seeks to understand the molecular players present in the metabolic program of T cells, how the TCR communicates with the metabolic machinery, and how these very early metabolic programs promote T cell effector function and cellular dynamics.
Therapeutic improvement of cellular therapies via metabolic reprogramming
Cellular therapies like TIL, CAR-T, or TCR-T are a form of adoptive cell therapy in which T cells are expanded or redirected to tumor antigens. These redirected T cells are then infused back into the patient where they seek out and kill tumor cells. The in vitro expansion phase of generating these therapies provides a unique opportunity to alter metabolic programs genetically, pharmacologically, or environmentally to support enhanced T cell stemness and efficacy in vivo.