Immunotherapy; Inflammation; Lymphocyte Activation; Medical Oncology; Neoplasms; Autoimmunity
Public Health Interests
Cancer; Immune functions
Rheumatic Diseases Research Core
I am interested in 1) molecular, biochemical and functional aspects of cell surface costimulatory and coinhibitory molecules and 2) translation of laboratory findings to treat human cancer and autoimmune diseases.
Specialized Terms: Lymphocyte activation and tolerance; Costimulation and coinhibition; tumor microenvironment; Immunotherapy of human cancer and autoimmune diseases
Extensive Research Description
Co-signaling molecules (also called costimulatory and coinhibitory molecules, immune checkpoint molecules) are essential for T cell communication with virtually all other host cells. During cell-to-cell contact, a specific recognition occurs between receptors and ligands of these molecules, which triggers intracellular biochemical signals and leads to the generation of immunological functions.
One hallmark of co-signaling molecules is that their function entirely depends on T cell receptor (TCR) signals. Co-signals positively and negatively control and modulate the initiation, expansion, functional maturation and execution, survival, and termination of T cell responses. The majority of co-signaling molecules are members of the immunoglobulin (Ig) and tumor necrosis factor (TNF) superfamilies. Our laboratory has identified a series of co-signaling molecules in both the B7-CD28 family (B7-H1/PD-L1, B7-H2/ICOSL, B7-DC/PD-L2, B7-H3 and B7-H4/B7x/B7S1) and the tumor necrosis factor (TNF) superfamily (CD137, LIGHT/HVEM) and characterized their biochemical pathways and immunological functions. We use monoclonal antibodies, recombinant co-signaling molecules, and gene knockouts to specifically manipulate co-signaling molecules.
Using mouse models, we have demonstrated the role of these co-signaling molecules in the pathogenesis and progression of various diseases, including cancer, autoimmune diseases, viral infections, and transplantation rejection. We have also developed several monoclonal antibodies which specifically stimulate (CD137) or inhibit (B7-H1, B7-H4) co-signaling molecule functions. These studies have laid the foundation for clinical trials that treat advanced cancer patients (anti-B7-H1/PD-L1, anti-PD-1, anti-CD137 antibodies) and autoimmune diseases (B7-H4Ig fusion protein). Ample evidence now supports that new strategies can be developed by precisely manipulating these cell surface molecular pathways to selectively block or promote T cell immunity in vivo as an approach to treat human diseases.
Currently, our laboratory is focusing on:
- The identification and characterization of new cell surface co-signaling molecules that control T cell priming, expansion, differentiation, memory, and survival: We have developed a Receptor Array system that rapidly identifies cell surface receptor-ligand interactions (Yao et al, Immunity, 2011). In combination with bioinformatic analysis, we perform genome-wide searches for new receptor-ligand interactions that are expressed during specific stages of T cell activation in response to antigen. These newly identified receptor-ligands will then be further characterized for their immunological function.
- The identification of intracellular biochemical pathways which determine the functional outcome of cell surface co-signaling: It is often difficult to interpret functional outcomes with specific intracellular signaling pathways due to the diverse effects that co-signaling can have on immune cells. We are developing new approaches to dissect complex signaling pathways that link cell surface co-signaling to extracellular immunological functions.
- Dissecting the mechanisms by which tumors escape the immune response: We are interested in the cellular and molecular mechanisms that determine a successful vs. a failed immune response in both animal models and human specimens, especially in the context of clinical trials that block the B7-H1/PD-1 pathway to treat human cancers.
-To understand the mechanisms of the B7-H1/PD-1 coinhibitory pathway in the evasion of tumor immunity
-Identification of new co-signaling (costimulatory and coinhibitory) molecules and their interactions
-Functional characterization of co-signaling molecules and their roles in the generation, development and regulation of immune responses to antigens
-Development of new approaches targeting new co-signaling pathways for the treatment of cancer, autoimmune diseases, inflammation and transplantation rejection in animal models
-Human immunology study to understand mechanisms of co-signal molecule-based therapy in cancer patients
Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity.
Flies DB, Han X, Higuchi T, Zheng L, Sun J, Ye JJ, Chen L. Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity. The Journal Of Clinical Investigation 2014, 124:1966-75.
B7-H5 costimulates human T cells via CD28H.
Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, Phennicie RT, Flies SJ, Broadwater M, Ruff W, Taube JM, Zheng L, Luo L, Zhu G, Chen J, Chen L. B7-H5 costimulates human T cells via CD28H. Nature Communications 2013, 4:2043.
Molecular mechanisms of T cell co-stimulation and co-inhibition.
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews. Immunology 2013, 13:227-42.
Advances in targeting cell surface signalling molecules for immune modulation.
Yao S, Zhu Y, Chen L. Advances in targeting cell surface signalling molecules for immune modulation. Nature Reviews. Drug Discovery 2013, 12:130-46.
Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Translational Medicine 2012, 4:127ra37.
Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future.
Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. The Journal Of Clinical Investigation 2015, 125:3384-91.
B7-h2 is a costimulatory ligand for CD28 in human.
Yao S, Zhu Y, Zhu G, Augustine M, Zheng L, Goode DJ, Broadwater M, Ruff W, Flies S, Xu H, Flies D, Luo L, Wang S, Chen L. B7-h2 is a costimulatory ligand for CD28 in human. Immunity 2011, 34:729-40.
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Science Translational Medicine 2016, 8:328rv4.
Full List of PubMed Publications
- Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, Syrigos K, Toki M, Zhao H, Chen L, Herbst RS, Schalper KA: Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer. Clin Cancer Res. 2018 Apr 1; 2017 Dec 4. PMID: 29203588
- Chen L, Azuma T, Yu W, Zheng X, Luo L, Chen L: B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U S A. 2018 Mar 20; 2018 Mar 5. PMID: 29507197
- Xiao Q, Wu J, Wang WJ, Chen S, Zheng Y, Yu X, Meeth K, Sahraei M, Bothwell ALM, Chen L, Bosenberg M, Chen J, Sexl V, Sun L, Li L, Tang W, Wu D: DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med. 2018 Mar; 2018 Feb 12. PMID: 29431745
- Lu N, Li Y, Zhang Z, Xing J, Sun Y, Yao S, Chen L: Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4. Nat Commun. 2018 Feb 21; 2018 Feb 21. PMID: 29467366
- Zhang J, Song K, Wang J, Li Y, Liu S, Dai C, Chen L, Wang S, Qin Z: S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor immunity. Oncoimmunology. 2018; 2018 Jan 23. PMID: 29632708
- Drabczyk-Pluta M, Werner T, Hoffmann D, Leng Q, Chen L, Dittmer U, Zelinskyy G: Granulocytic myeloid-derived suppressor cells suppress virus-specific CD8+ T cell responses during acute Friend retrovirus infection. Retrovirology. 2017 Aug 23; 2017 Aug 23. PMID: 28835242
- Kluger HM, Zito CR, Turcu G, Baine MK, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, Cohen JV, Jilaveanu LB: PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clin Cancer Res. 2017 Aug 1; 2017 Feb 21. PMID: 28223273
- Wang Q, He J, Flies DB, Luo L, Chen L: Programmed death one homolog maintains the pool size of regulatory T cells by promoting their differentiation and stability. Sci Rep. 2017 Jul 20; 2017 Jul 20. PMID: 28729608
- Nie X, Chen W, Zhu Y, Huang B, Yu W, Wu Z, Guo S, Zhu Y, Luo L, Wang S, Chen L: B7-DC (PD-L2) costimulation of CD4+ T-helper 1 response via RGMb. Cell Mol Immunol. 2017 May 8; 2017 May 8. PMID: 28479601
- Liu H, Li X, Hu L, Zhu M, He B, Luo L, Chen L: A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma. Cell Mol Immunol. 2017 May 8; 2017 May 8. PMID: 28479600
- Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Altan M, Velcheti V, Gaule P, Sanmamed MF, Chen L, Herbst RS, Rimm DL: Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer. Clin Cancer Res. 2017 Jan 15; 2016 Jul 20. PMID: 27440266
- Zhang Y, Chen L: Classification of Advanced Human Cancers Based on Tumor Immunity in the MicroEnvironment (TIME) for Cancer Immunotherapy. JAMA Oncol. 2016 Nov 1. PMID: 27490017
- Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, Semeraro M, Jégou S, Flores C, Chen L, Kwon BS, Borg C, Weide B, Aubin F, Dalle S, Kohrt H, Ayyoub M, Kroemer G, Marabelle A, Cavalcanti A, Eggermont A, Zitvogel L: Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis. J Invest Dermatol. 2016 May; 2016 Jan 29. PMID: 26829031
- Zhu Y, Yao S, Augustine MM, Xu H, Wang J, Sun J, Broadwater M, Ruff W, Luo L, Zhu G, Tamada K, Chen L: Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM. Sci Adv. 2016 Apr; 2016 Apr 8. PMID: 27152329
- Zou W, Wolchok JD, Chen L: PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016 Mar 2. PMID: 26936508
- Sun H, Luo L, Lal B, Ma X, Chen L, Hann CL, Fulton AM, Leahy DJ, Laterra J, Li M: A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis. Nat Commun. 2016 Feb 4; 2016 Feb 4. PMID: 26842342
- Byers JT, Paniccia A, Kaplan J, Koenig M, Kahn N, Wilson L, Chen L, Schulick RD, Edil BH, Zhu Y: Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer. Ann Surg Oncol. 2015 Dec; 2014 Dec 18. PMID: 25519928
- Akhmetzyanova I, Drabczyk M, Neff CP, Gibbert K, Dietze KK, Werner T, Liu J, Chen L, Lang KS, Palmer BE, Dittmer U, Zelinskyy G: PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing. PLoS Pathog. 2015 Oct; 2015 Oct 20. PMID: 26484769
- Baine MK, Turcu G, Zito CR, Adeniran AJ, Camp RL, Chen L, Kluger HM, Jilaveanu LB: Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget. 2015 Sep 22. PMID: 26317902
- Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL, Sznol M, Rimm DL, Chen L, Jilaveanu LB: Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clin Cancer Res. 2015 Jul 1; 2015 Mar 18. PMID: 25788491
- Weigelin B, Bolaños E, Teijeira A, Martinez-Forero I, Labiano S, Azpilikueta A, Morales-Kastresana A, Quetglas JI, Wagena E, Sánchez-Paulete AR, Chen L, Friedl P, Melero I: Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. Proc Natl Acad Sci U S A. 2015 Jun 16; 2015 Jun 1. PMID: 26034288
- Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, Chen L, Chang J, Chung DH, Choi I, Ha SJ: PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J Immunol. 2015 Jun 15; 2015 May 1. PMID: 25934860
- Luo L, Zhu G, Xu H, Yao S, Zhou G, Zhu Y, Tamada K, Huang L, Flies AD, Broadwater M, Ruff W, van Deursen JM, Melero I, Zhu Z, Chen L: B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets. PLoS One. 2015; 2015 Jun 11. PMID: 26065426
- Flies DB, Higuchi T, Chen L: Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens. J Immunol. 2015 Jun 1; 2015 Apr 27. PMID: 25917101
- McKay JT, Egan RP, Yammani RD, Chen L, Shin T, Yagita H, Haas KM: PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cell-intrinsic mechanism. J Immunol. 2015 Mar 1; 2015 Jan 26. PMID: 25624454
- Apetoh L, Smyth MJ, Drake CG, Abastado JP, Apte RN, Ayyoub M, Blay JY, Bonneville M, Butterfield LH, Caignard A, Castelli C, Cavallo F, Celis E, Chen L, Colombo MP, Comin-Anduix B, Coukos G, Dhodapkar MV, Dranoff G, Frazer IH, Fridman WH, Gabrilovich DI, Gilboa E, Gnjatic S, Jäger D, Kalinski P, Kaufman HL, Kiessling R, Kirkwood J, Knuth A, Liblau R, Lotze MT, Lugli E, Marincola F, Melero I, Melief CJ, Mempel TR, Mittendorf EA, Odun K, Overwijk WW, Palucka AK, Parmiani G, Ribas A, Romero P, Schreiber RD, Schuler G, Srivastava PK, Tartour E, Valmori D, van der Burg SH, van der Bruggen P, van den Eynde BJ, Wang E, Zou W, Whiteside TL, Speiser DE, Pardoll DM, Restifo NP, Anderson AC: Consensus nomenclature for CD8+ T cell phenotypes in cancer. Oncoimmunology. 2015 Apr; 2015 Feb 25. PMID: 26137416
- Deng R, Cassady K, Li X, Yao S, Zhang M, Racine J, Lin J, Chen L, Zeng D: B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease. J Immunol. 2015 Jan 15; 2014 Dec 8. PMID: 25488990
- Wang J, Chen L: Myeloid cells' evasion of melanoma immunity. J Invest Dermatol. 2014 Nov. PMID: 25318429
- Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, Zhang X, Yi X, Dwyer D, Lin W, Diao L, Wang J, Roybal J, Patel M, Ungewiss C, Peng D, Antonia S, Mediavilla-Varela M, Robertson G, Suraokar M, Welsh JW, Erez B, Wistuba II, Chen L, Peng D, Wang S, Ullrich SE, Heymach JV, Kurie JM, Qin FX: Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014 Oct 28; 2014 Oct 28. PMID: 25348003
- Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA: Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014 Oct 1; 2014 Apr 8. PMID: 24714771
- Fujiwara H, Maeda Y, Kobayashi K, Nishimori H, Matsuoka K, Fujii N, Kondo E, Tanaka T, Chen L, Azuma M, Yagita H, Tanimoto M: Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease. J Immunol. 2014 Sep 1; 2014 Jul 30. PMID: 25080485
- Yao S, Chen L: PD-1 as an immune modulatory receptor. Cancer J. 2014 Jul-Aug. PMID: 25098286
- Sanmamed MF, Chen L: Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J. 2014 Jul-Aug. PMID: 25098285
- Chen L: From the guest editor: Tumor site immune modulation therapy. Cancer J. 2014 Jul-Aug. PMID: 25098284
- Wang X, Marr AK, Breitkopf T, Leung G, Hao J, Wang E, Kwong N, Akhoundsadegh N, Chen L, Mui A, Carr N, Warnock GL, Shapiro J, McElwee KJ: Hair follicle mesenchyme-associated PD-L1 regulates T-cell activation induced apoptosis: a potential mechanism of immune privilege. J Invest Dermatol. 2014 Mar; 2013 Sep 4. PMID: 24005055
- Scandiuzzi L, Ghosh K, Hofmeyer KA, Abadi YM, Lázár-Molnár E, Lin EY, Liu Q, Jeon H, Almo SC, Chen L, Nathenson SG, Zang X: Tissue-expressed B7-H1 critically controls intestinal inflammation. Cell Rep. 2014 Feb 27; 2014 Feb 13. PMID: 24529703
- Zhu Y, Chen L: CD137 as a biomarker for tumor-reactive T cells: finding gold in the desert. Clin Cancer Res. 2014 Jan 1; 2013 Oct 28. PMID: 24166912
- Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL: Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014 Jan; 2013 Nov 11. PMID: 24217091
- Sznol M, Chen L: Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--response. Clin Cancer Res. 2013 Oct 1; 2013 Sep 18. PMID: 24048329
- Chen L, Flies DB: Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013 Apr; 2013 Mar 8. PMID: 23470321
- Sznol M, Chen L: Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013 Mar 1. PMID: 23460533
- Yao S, Chen L: Adaptive resistance: a tumor strategy to evade immune attack. Eur J Immunol. 2013 Mar; 2013 Feb 4. PMID: 23381914
- Yao S, Zhu Y, Chen L: Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov. 2013 Feb. PMID: 23370250
- Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, Phennicie RT, Flies SJ, Broadwater M, Ruff W, Taube JM, Zheng L, Luo L, Zhu G, Chen J, Chen L: B7-H5 costimulates human T cells via CD28H. Nat Commun. 2013. PMID: 23784006
- Park JJ, Anand S, Zhao Y, Matsumura Y, Sakoda Y, Kuramasu A, Strome SE, Chen L, Tamada K: Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory. Cancer Immunol Immunother. 2012 Feb; 2011 Aug 30. PMID: 21877247
- Flies DB, Sandler BJ, Sznol M, Chen L: Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J Biol Med. 2011 Dec. PMID: 22180678
- Flies DB, Wang S, Xu H, Chen L: Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol. 2011 Aug 15; 2011 Jul 18. PMID: 21768399
- Yao S, Zhu Y, Zhu G, Augustine M, Zheng L, Goode DJ, Broadwater M, Ruff W, Flies S, Xu H, Flies D, Luo L, Wang S, Chen L: B7-h2 is a costimulatory ligand for CD28 in human. Immunity. 2011 May 27; 2011 Apr 28. PMID: 21530327
- Zhu Y, Yao S, Chen L: Cell surface signaling molecules in the control of immune responses: a tide model. Immunity. 2011 Apr 22. PMID: 21511182
- Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ: PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010 Jun; 2010 May 9. PMID: 20453843