Stefani Spranger

The Spranger lab is interested in understanding the mechanisms underlying the interaction between cancer and cells of the immune system. By using tumor mouse models, designed to mimic tumor progression in humans, the primary goal is to understand the co-evolution of the anti-tumor immune response and cancer. Understanding the interplay between tumor and immune cells will help to develop and improve effective immunotherapies against cancer.

CreER, LSLBrafV600E, PTENfl/fl, R26-LSL-SIY, R26-LSL-YFP). Tumor cells (YFP) are illustrated in green. Left, 48 hours post adoptive transfer; right 120h post adoptive transfer. 25x emulsion lens, Leica SP6.

Eradication of tumor lesion mediated by adoptively transferred in vitro-activated, tumor-specific 2C TCR-transgenic T cells. T cells were labeled with dark red fluorescent dye (red) and transferred into mice with melanoma lesions that are driven by BrafV600E and PTEN-deletions (Tyr:CreER, LSLBrafV600E, PTENfl/fl, R26-LSL-SIY, R26-LSL-YFP). Tumor cells (YFP) are illustrated in green. Left, 48 hours post adoptive transfer; right 120h post adoptive transfer. 25x emulsion lens, Leica SP6. 

The goal of the Spranger lab is to understand the molecular mechanisms of a range of tumor cell-intrinsic, tissue-specific or environmental factors directly impacting the interaction between cancer and the immune system. Understanding which permutations affect the anti-tumor immune response will answer thus far unanswered questions on the interplay between the immune system with the tumor and will facilitate the development of new rational therapeutic approaches. Over the last decade cancer immunotherapies, first and foremost checkpoint blockade therapy (anti-CTLA4 and anti-PD-1/PD-L1) has revolutionized cancer treatment. Despite the recent advances it should be noted that only a fraction of cancer patients responds towards immunotherapeutic interventions. Even for cancer types with a high response rate, only a fraction of patients are responding. The presence of CD8+ T cells, so-called cytolytic T cells, within the tumor microenvironment, is known to be the discriminating factor for the response towards checkpoint blockade. Most cancer types can be subdivided into T cell-inflamed and non-T cell-inflamed groups, based on the presence of CD8+ T cells. Thus far our knowledge on factors contributing to the exclusion of immune cells is limited. Studies in melanoma have provided insights that tumor cell-intrinsic activation of certain signaling pathways, WNT/β-catenin and PI3K, are linked to the loss of T cell infiltration. Specifically, activation of β-catenin results in a local reduction of a dendritic cell subset specialized in the activation of CD8+ T cells. Furthermore, depletion of only this subset of dendritic cells renders the previously T cell-inflamed into a non-T cell-inflamed tumor microenvironment, illustrating the complexity of the tumor microenvironment. The Spranger lab aims to understand what additional factors contribute to T cell exclusion from the tumor microenvironment, including tumor cell-intrinsic, tissue-macroenvironmental or environmental factors (e.g. infections). The lab focuses on lung cancer and pancreatic cancer, representing immunotherapy-sensitive and resistant cancer types, respectively. By understanding the factors contributing to a productive or malfunctioning anti-tumor immune response, factor determining the presence or absence of anti-tumor immune cells from the tumor microenvironment, will guide us in improving existing immunotherapeutic therapies or develop novel combination therapies.

Selected Publications:

1. Density of immunogenic antigens does not explain the presence or absence of the T cell-inflamed tumor microenvironment in melanoma. Spranger S*, Luke JJ*, Bao R, Zha Y, Hernandez K, Li Y, Gajewski AP, Andrade J, Gajewski TF. Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7759-E7768

2. Molecular Drivers of the Non-T Cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer. Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg GD, Gajewski TF. Cancer Immunol Res. 2016 Jul;4(7):563-8. doi: 10.1158/2326-6066.CIR-15-0274. PubMed PMID: 27197067; PubMed Central PMCID: PMC4943758.

3. Engineering Active IKKβ in T Cells Drives Tumor Rejection. Evaristo C, Spranger S, Barnes SE, Miller ML, Molinero LL, Locke FL, Gajewski TF, Alegre ML. J Immunol. 2016 Apr 1;196(7):2933-8. doi: 10.4049/jimmunol.1501144. PubMed PMID: 26903482; PubMed Central PMCID: PMC4799771.

4. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, Williams LJ, Deng W, Chen G, Mbofung R, Lazar AJ, Torres Cabala CA, Cooper ZA, Chen PL, Tieu TN, Spranger S, Yu X, Bernatchez C, Forget MA, Haymaker C, Amaria R, McQuade JL, Glitza IC, Cascone T, Li H, Kwong LN, Heffernan TP, Hu J, Bassett RL Jr, Bosenberg MW, Woodman SE, Overwijk WW, Lizee G, Roszik J, Gajewski TF, Wargo JA, Gershenwald JE, Radvanyi LG, Davies MA, Hwu P, Cancer Discov. 2015 Dec 8.

5. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Spranger S, Bao R, and Gajewski TF, Nature. 2015 Jul 9;523(7559):231-5. doi: 10.1038/nature14404. Epub 2015 May 11.

6. STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung M, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre M, Gajewski TF, Immunity. 2014 Nov 20;41(5):830-42. doi: 10.1016/j.immuni.2014.10.017. Epub 2014 Nov 5.

7. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. Spranger S, Koblish H, Horton B, Scherle P, Newton R, Gajewski TF, J Immunother Cancer. 2014 Feb 18;2:3. doi: 10.1186/2051-1426-2-3. eCollection 2014.

8. Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells. Spranger S*, Spaapen RM*, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF, Sci Transl Med. 2013 Aug 28;5(200):200ra116. doi: 10.1126/scitranslmed.3006504.

9. T cell receptor-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo. Spranger S, Jeremias I, Wilde S, Leisegang M, Stärk L, Mosetter B, Uckert W, Heemskerk MH, Schendel DJ and Frankenberger B, Blood. 2012 Apr 12;119(15):3440-9. doi: 10.1182/blood-2011-06-357939. Epub 2012 Feb 27.

10. Generation of Th1-polarizing dendritic cells using the TLR7/8 agonist CL075. Spranger S, Javorovic M, Bürdek M, Wilde S, Mosetter B, Tippmer S, Bigalke I, Geiger C, Schendel DJ, Frankenberger B, J Immunol. 2010 Jul 1;185(1):738-47. doi: 10.4049/jimmunol.1000060. Epub 2010 May 28.

* authors contributed equally