Signalveje for non-effektorceller

CSF1R: Stimulerer immunsuppression i tumors mikromiljø

Kolonistimulerende faktor 1 receptor (CSF1R Colony-Stimulating Factor 1 Receptor) er en receptor på celleoverfladen, som udtrykkes af makrofager og andre celler af myeloid afstamning.1

I tumors mikromiljø ændrer nogle af makrofagerne deres antitumor-aktivitet til protumor-aktivitet.2 De kaldes tumor-associerede makrofager (TAM’er). TAM’er fremmer cancercellernes overlevelse og immunosuppression og understøtter på den måde tumorvækst.2

 

CSF1, liganden for CSF1R, er en betydningsfuld regulator for makrofagernes differentiering og funktion.3 Hos cancerpatienter er høje CSF1-koncentrationer associeret med en dårlig prognose.3,4 Musemodeller har vist, at tumorceller anvender CSF1 til at stimulere makrofager til TAM udvikling.5

Blokering af CSF1R, hvorved CSF1 fratages dets målreceptor, har i prækliniske studier medført reduceret TAM og forbedret T-cellerespons.6,7


CD73: Skubber immunbalancen mod et mere supprimerende miljø

CD73 er et enzym på celleoverfladen på regulatoriske T-celler (Treg-celler). Her er det et vigtigt checkpoint i omdannelsen af immunaktiverende ATP til immunsupprimerende adenosin.8 Treg-celler virker ved at hæmme immunresponset, og frigivelsen af adenosin hjælper Treg-celler med at lukke ned for immunaktivitet.9,10

Cancer udnytter CD73’s evne til at svække antitumorimmunitet. I lighed med Tregs kan tumorceller udtrykke CD73 og frigive adenosin i tumors mikromiljø.11-13 I cellulære studier er adenosin en kraftig hæmmer af antitumorimmunrespons, herunder proliferation og udskillelsen af cytokiner.8

Præklinisk forskning har identificeret tumorafledt CD73 som værende en medvirkende faktor ved immunundvigelse ved cancer. Derudover kan hæmning af CD73-aktivitet stimulere T-celleaktivitet.14


IDO: Nedbryder immuncellernes brændstof

IDO (Indoleamine-2,3-dioxygenase-1) er et intracellulært enzym, som udløser nedbrydning af tryptofan i tumors mikromiljø.15,16 Tryptofan er en aminosyre, der er essentiel for celleoverlevelse.17 Under normale omstændigheder kan IDO’s metabolisme af tryptofan holde T-cellernes immunrespons under kontrol.18

Tumorceller er i stand til at kapre denne immunsupprimerende proces. De har udviklet evnen til at opregulere IDO-aktivitet for at hæmme T-cellernes funktion og sikre, at de selv overlever.19,20 Forhøjet IDO er forbundet med en dårlig prognose ved cancer.21,22

Tumorceller anvender IDO til at inducere immuntolerance ved hjælp af 2 forskellige mekanismer:

  • Direkte ved at forhindre de tumorreaktive T-celler i at få det tryptophan, de behøver for at overleve og fungere18
  • Indirekte ved at udløse udvikling af regulatoriske T-celler (Treg-celler), som har til formål at hæmme immunrespons22,23

I prækliniske studier er det vist, at blokering af IDO kan reducere antallet af Treg-celler og genoprette de cytotoksiske T-cellers funktion.22,24


Der forskes fortsat i at forstå disse signalveje.

Referencer

1. Stanley ER, Chitu V. CSF-1 Receptor Signaling in Myeloid Cells. Cold Spring Harb Perspect Biol. 2014;6:a021857. 2. Noy R, Pollard JW. Tumor-Associated Macrophages: From Mechanisms to Therapy. Immunity. 2014;41(1):49-61. 3. Richardson E, Uglehus RD, Johnsen SH, Busnd LT. Macrophage-Colony Stimulating Factor (CSF1) Predicts Breast Cancer Progression and Mortality. Anticancer Res. 2015;35(2):865-874. 4. Yang L, Wu Q, Xu L, et al. Increased expression of colony stimulating factor-1 is a predictor of poor prognosis in patients with clear-cell renal cell carcinoma BMC Cancer. 2015;15:67. doi:10.1186/s12885-015-1076-5. 5. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models. Cancer Res. 2014;74(18):5057-5069. 6. Ries CH, Cannarile MA, Hoves S, et al. Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy. Cancer Cell. 2014;25:846-859. 7. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses. Cancer Res. 2013;73:1128-1141. 8. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5’-adenosine monophosphate to adenosine. J Immunol. 2006;177(10):6780-6786. 9. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257-1265. 10. Picher M, Burch LH, Hirsh AJ, Spychala J, Boucher RC. Ecto 5’-nucleotidase and nonspecific alkaline phosphatase. J Biol Chem. 2003;278(15):13468-13479. 11. Häusler SF, del Barrio IM, Strochschein J, et al. Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother. 2011;60(10):1405-1418. 12. Serra S, Horenstein AL, Vaisitti T, et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood. 2011;118(23):6141-6152. 13. Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103(35):13132-13137. 14. Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci USA. 2010;107(4):1547-1552. 15. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20(10):469-473. 16. Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297(5588):1867-1870. 17. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774. 18. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189(9):1363-1372. 19. Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58(1):153-157. 20. Liu P, Xie BL, Cai SH, et al. Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes. BMC Cancer. 2009;9:416. doi:10.1186/1471-2407-9-416. 21. Jia Y, Wang H, Wang Y, et al. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer. 2015;137(5):1095-1106. 22. Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18(22):6110-6121. 23. Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752-6761. 24. Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269-1274.