PDCD1LG2 explained

Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the PDCD1LG2 gene.^{[1] [2]} PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273). PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response.^[3] PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).

Structure

PD-L2 is a cell surface receptor belonging to the B7 protein family.^[4] It consists of both an immunoglobulin-like variable domain and an immunoglobulin-like constant domain in the extracellular region, a transmembrane domain, and a cytoplasmic domain. PD-L2 shares considerable sequence homology with other B7 proteins,^[5] but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT.

The crystal structure of murine PD-L2 bound to murine PD-1 has been determined.^[6] as well as the structure of the hPD-L2/mutant hPD-1 complex.^[7]

Expression

Profile

PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages.^[8] Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells.^{[9] [10]} PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas.^[11] Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma. PD-L2 mRNA is widely expressed and not enriched in any particular tissue.

Regulation

Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro. IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.

Function

PD-L2 binds to its receptor PD-1 with dissociation constant K_d of 11.3 nM.^[12] Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity.^[13] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production. Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis. Unlike PD-L1, PD-L2 has been shown activate the immune system. PD-L2 triggers IL-12 production in murine dendritic cells leading to T cell activation. Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation.

Clinical significance

PD-L2, PD-L1, and PD-1 expressions are important in the immune response to certain cancers. Due to their role in suppressing the adaptive immune system, efforts have been made to block PD-1 and PD-L1, resulting in FDA approved inhibitors for both (see pembrolizumab, nivolumab, atezolizumab). There are still no FDA approved inhibitors for PD-L2 as of 2019.^[14]

The direct role of PD-L2 in cancer progression and immune-tumor microenvironment regulation is not as well studied as the role of PD-L1.^[15] In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses.^[16]

Indirectly, PD-L2 may have utility as a biomarker or prognostic indicator. PD-L2 expression has been shown to predict response to PD-1 blockade with pembrolizumab independently of PD-L1 expression. However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses^{[17] [18] [19]} and other studies suggesting it predicts positive prognoses.^[20]

Further reading

• Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H . 6 . B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells . The Journal of Experimental Medicine . 193 . 7 . 839–46 . April 2001 . 11283156 . 2193370 . 10.1084/jem.193.7.839 .
• Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ . 6 . Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production . Journal of Immunology . 170 . 3 . 1257–66 . February 2003 . 12538684 . 10.4049/jimmunol.170.3.1257 . free .
• Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M . 6 . Differential binding properties of B7-H1 and B7-DC to programmed death-1 . Biochemical and Biophysical Research Communications . 307 . 3 . 672–7 . August 2003 . 12893276 . 10.1016/S0006-291X(03)01257-9 .
• Tsushima F, Iwai H, Otsuki N, Abe M, Hirose S, Yamazaki T, Akiba H, Yagita H, Takahashi Y, Omura K, Okumura K, Azuma M . 6 . Preferential contribution of B7-H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses . European Journal of Immunology . 33 . 10 . 2773–82 . October 2003 . 14515261 . 10.1002/eji.200324084 . 34992725 . free .
• Aramaki O, Shirasugi N, Takayama T, Shimazu M, Kitajima M, Ikeda Y, Azuma M, Okumura K, Yagita H, Niimi M . 6 . Programmed death-1-programmed death-L1 interaction is essential for induction of regulatory cells by intratracheal delivery of alloantigen . Transplantation . 77 . 1 . 6–12 . January 2004 . 14724428 . 10.1097/01.TP.0000108637.65091.4B . 25360886 .
• He XH, Liu Y, Xu LH, Zeng YY . Cloning and identification of two novel splice variants of human PD-L2 . Acta Biochimica et Biophysica Sinica . 36 . 4 . 284–9 . April 2004 . 15253154 . 10.1093/abbs/36.4.284 . free .
• Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–24 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
• Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y . 6 . Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer . Clinical Cancer Research . 11 . 8 . 2947–53 . April 2005 . 15837746 . 10.1158/1078-0432.CCR-04-1469 . free .
• Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML . PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion . European Journal of Immunology . 35 . 12 . 3561–9 . December 2005 . 16278812 . 10.1002/eji.200526347 . 43876326 . free .
• Pfistershammer K, Klauser C, Pickl WF, Stöckl J, Leitner J, Zlabinger G, Majdic O, Steinberger P . 6 . No evidence for dualism in function and receptors: PD-L2/B7-DC is an inhibitory regulator of human T cell activation . European Journal of Immunology . 36 . 5 . 1104–13 . May 2006 . 16598819 . 2975063 . 10.1002/eji.200535344 .
• Abelson AK, Johansson CM, Kozyrev SV, Kristjansdottir H, Gunnarsson I, Svenungsson E, Jönsen A, Lima G, Scherbarth HR, Gamron S, Allievi A, Palatnik SA, Alvarellos A, Paira S, Graf C, Guillerón C, Catoggio LJ, Prigione C, Battagliotti CG, Berbotto GA, García MA, Perandones CE, Truedsson L, Steinsson K, Sturfelt G, Pons-Estel B, Alarcón-Riquelme ME . 6 . No evidence of association between genetic variants of the PDCD1 ligands and SLE . Genes and Immunity . 8 . 1 . 69–74 . January 2007 . 17136123 . 10.1038/sj.gene.6364360 . free .
• Mataki N, Kikuchi K, Kawai T, Higashiyama M, Okada Y, Kurihara C, Hokari R, Kawaguchi A, Nagao S, Kondo T, Itoh K, Miyakawa H, Miura S . 6 . Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases . The American Journal of Gastroenterology . 102 . 2 . 302–12 . February 2007 . 10.1111/j.1572-0241.2006.00948.x . 17311651 . 8083797 .
• Wang SC, Lin CH, Ou TT, Wu CC, Tsai WC, Hu CJ, Liu HW, Yen JH . 6 . Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus . The Journal of Rheumatology . 34 . 4 . 721–5 . April 2007 . 17343323 . 10.1093/rheumatology/34.8.721 .

Notes and References

1. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ . 6 . PD-L2 is a second ligand for PD-1 and inhibits T cell activation . Nature Immunology . 2 . 3 . 261–8 . March 2001 . 11224527 . 10.1038/85330 . 27659586 .
2. Web site: Entrez Gene: PDCD1LG2 programmed cell death 1 ligand 2.
3. McDermott DF, Atkins MB . PD-1 as a potential target in cancer therapy . Cancer Medicine . 2 . 5 . 662–73 . October 2013 . 24403232 . 3892798 . 10.1002/cam4.106 .
4. Chen L . Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity . Nature Reviews. Immunology . 4 . 5 . 336–47 . May 2004 . 15122199 . 10.1038/nri1349 . 33548210 .
5. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H . 6 . B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells . The Journal of Experimental Medicine . 193 . 7 . 839–46 . April 2001 . 11283156 . 2193370 . 10.1084/jem.193.7.839 .
6. Lázár-Molnár E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC . Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2 . Proceedings of the National Academy of Sciences of the United States of America . 105 . 30 . 10483–8 . July 2008 . 18641123 . 10.1073/pnas.0804453105 . 2492495 . free .
7. Tang S, Kim PS . A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery . Proceedings of the National Academy of Sciences of the United States of America . 116 . 49 . 24500–24506 . December 2019 . 31727844 . 10.1073/pnas.1916916116 . 6900541 . 2019PNAS..11624500T . free .
8. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ . The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection . Nature Immunology . 8 . 3 . 239–45 . March 2007 . 17304234 . 10.1038/ni1443 . 8749576 .
9. Messal N, Serriari NE, Pastor S, Nunès JA, Olive D . PD-L2 is expressed on activated human T cells and regulates their function . Molecular Immunology . 48 . 15–16 . 2214–9 . September 2011 . 21752471 . 10.1016/j.molimm.2011.06.436 . 33134166 .
10. Lesterhuis WJ, Steer H, Lake RA . PD-L2 is predominantly expressed by Th2 cells . Molecular Immunology . 49 . 1–2 . 1–3 . October 2011 . 22000002 . 10.1016/j.molimm.2011.09.014 .
11. Web site: Tissue expression of PDCD1LG2 . The Human Protein Atlas . 2020-03-05.
12. Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA, Olive D . PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1 . International Immunology . 22 . 8 . 651–60 . August 2010 . 20587542 . 10.1093/intimm/dxq049 . 3168865 .
13. Zhang Y, Chung Y, Bishop C, Daugherty B, Chute H, Holst P, Kurahara C, Lott F, Sun N, Welcher AA, Dong C . 6 . Regulation of T cell activation and tolerance by PDL2 . Proceedings of the National Academy of Sciences of the United States of America . 103 . 31 . 11695–700 . August 2006 . 16864790 . 10.1073/pnas.0601347103 . 1544232 . 2006PNAS..10311695Z . free .
14. Web site: Search of: PDCD1LG2 - List Results - ClinicalTrials.gov. clinicaltrials.gov. en. 2020-03-04.
15. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, Lunceford J, Cheng J, Chow LQ, Seiwert TY, Handa M, Tomassini JE, McClanahan T . 6 . PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer . Clinical Cancer Research . 23 . 12 . 3158–3167 . June 2017 . 28619999 . 10.1158/1078-0432.CCR-16-1761 . free .
16. Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, Kinoshita F, Akiba J, Kashiwagi E, Takeuchi A, Irie T, Tatsugami K, Hoshino T, Eto M, Nishikawa H . 6 . Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity . Clinical Cancer Research . 25 . 15 . 4808–4819 . August 2019 . 31076547 . 10.1158/1078-0432.CCR-18-3991 . free . 2324/4475014 . free .
17. Wang ZL, Li GZ, Wang QW, Bao ZS, Wang Z, Zhang CB, Jiang T . PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor . Oncoimmunology . 8 . 2 . e1541535 . 2019 . 30713802 . 6343813 . 10.1080/2162402X.2018.1541535 .
18. Yang H, Zhou X, Sun L, Mao Y . Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis . en . Frontiers in Oncology . 9 . 47 . 2019 . 30891423 . 10.3389/fonc.2019.00047 . 6413700 . free .
19. Tobin JW, Keane C, Gunawardana J, Mollee P, Birch S, Hoang T, Lee J, Li L, Huang L, Murigneux V, Fink JL, Matigian N, Vari F, Francis S, Kridel R, Weigert O, Haebe S, Jurinovic V, Klapper W, Steidl C, Sehn LH, Law SC, Wykes MN, and Gandhi MK . 6 . Progression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration. Journal of Clinical Oncology . 37 . 34 . 3300–3309 . 2019 . 31570492 . 10.1200/JCO.18.02365 . 6784528 . free .
20. Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, Bullock TN, Slingluff CL . 6 . PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome . Oncoimmunology . 5 . 11 . e1235107 . 2016 . 27999753 . 5139635 . 10.1080/2162402X.2016.1235107 .