Signalveje for non-effektorceller

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.^11,12,13 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 immunrespons^22,23

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

Relateret

Inspiration

Referencer:

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• 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.
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• 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.
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