Immuncheckpoint

Immuncheckpoints oder Immun-Checkpoints (IC), sind Rezeptoren auf der Membran von T-Lymphozyten, die deren Immunantwort dämpfen (antiinflammatorische IC) oder steigern (proinflammatorische IC) können. Sie modulieren also die Immunreaktion, beispielsweise um körpereigene Zellen vor dem Angriff des Immunsystems zu schützen.

Zu den Rezeptoren gehören passende Liganden, die von anderen Zellen präsentiert oder freigesetzt werden. Bei vielen Tumoren sind diese Proteine im Zuge einer Immunevasion hochreguliert, und die Tumorzellen werden vom Immunsystem toleriert. Immuncheckpoint-Inhibitoren sind Substanzen, die dauerhaft an die Checkpoints binden, sie inhibieren, und damit die Immunantwort verstärken. Sie werden im Zuge einer Krebsimmuntherapie gegen antiinflammatorische Immuncheckpoints zur Behandlung von Tumoren eingesetzt, wodurch die Immunreaktion gegen den Tumor verstärkt wird.

Antiinflammatorische (entzündungsdämpfende) Immuncheckpoints

Zu den entzündungshemmenden Immuncheckpoints zählen der A2AR,[1] B7-H3 (CD276),[2][3] B7-H4 (synonym VTCN1), BTLA,[4] CTLA-4,[5] IDO,[6] KIR, LAG3,[7] PD-1,[8] TIM-3[9] und VISTA (V-domain Ig suppressor of T cell activation).[10]

Proinflammatorische (entzündungssteigernde) Immuncheckpoints

Fünf Vertreter proinflammatorischer Immuncheckpoints entstammen der TNF-Rezeptor-Superfamilie (CD27,[11] CD40,[12] OX40,[13] GITR[14] und CD137[15]), während zwei zur B7-CD28-Superfamilie gehören (CD28[16] und ICOS[17]).

Literatur

P. Sharma, J. P. Allison: Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. In: Cell. Band 161, Nummer 2, April 2015, S. 205–214, doi:10.1016/j.cell.2015.03.030, PMID 25860605.
A. Śledzińska, L. Menger, K. Bergerhoff, K. S. Peggs, S. A. Quezada: Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy. In: Molecular oncology. [elektronische Veröffentlichung vor dem Druck] Oktober 2015, doi:10.1016/j.molonc.2015.10.008, PMID 26578451.
E. Marcq, P. Pauwels, J. P. van Meerbeeck, E. L. Smits: Targeting immune checkpoints: New opportunity for mesothelioma treatment? In: Cancer treatment reviews. Band 41, Nummer 10, Dezember 2015, S. 914–924, doi:10.1016/j.ctrv.2015.09.006, PMID 26433514.

Einzelnachweise

RD Leone, YC Lo, JD Powell: A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. In: Comput Struct Biotechnol J.. 13, 8. April 2015, S. 265–. PMID 25941561.
AI Chapoval, J Ni, JS Lau, RA Wilcox, DB Flies, D Liu, H Dong, GL Sica, G Zhu, K Tamada, L Chen: B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. In: Nat Immunol.. 2, Nr. 3, 1. März 2001, S. 269–74. PMID 11224528.
J Leitner, C Klauser, WF Pickl, J Stöckl, O Majdic, AF Bardet, DP Kreil, C Dong, T Yamazaki, G Zlabinger, K Pfistershammer, P Steinberger: B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. In: Eur J Immunol.. 39, Nr. 7, 1. Juli 2009, S. 1754–64. PMID 19544488.
L Derré, JP Rivals, C Jandus, S Pastor, D Rimoldi, P Romero, O Michielin, D Olive, DE Speiser: BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. In: J Clin Invest.. 120, Nr. 1, 1. Januar 2010, S. 157–67. PMID 20038811.
P Kolar, K Knieke, JK Hegel, D Quandt, GR Burmester, H Hoff, Brunner-Weinzierl MC: CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. In: Arthritis Rheum.. 60, Nr. 1, 1. Januar 2009, S. 123–32. PMID 19116935.
GC Prendergast, C Smith, S Thomas, Mandik-Nayak L, Laury-Kleintop L, R Metz, AJ Muller: Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. In: Cancer Immunol Immunother.. 63, Nr. 7, 1. Juli 2014, S. 721–35. PMID 24711084.
CT Huang, CJ Workman, D Flies, X Pan, AL Marson, G Zhou, EL Hipkiss, S Ravi, J Kowalski, HI Levitsky, JD Powell, DM Pardoll, CG Drake, DA Vignali: Role of LAG-3 in regulatory T cells. In: Immunity.. 21, Nr. 4, 1. Oktober 2004, S. :503–13. PMID 15485628.
GK Philips, M Atkins: Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. In: Int Immunol.. 27, Nr. 1, 1. Januar 2015, S. 39–46. PMID 25323844.
WD Hastings, DE Anderson, N Kassam, K Koguchi, EA Greenfield, SC Kent, XX Zheng, TB Strom, DA Hafler, VK Kuchroo: TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. In: Eur J Immunol.. 39, Nr. 9, 1. September 2009, S. 2492–501. PMID 19676072.
L Wang, R Rubinstein, JL Lines, A Wasiuk, C Ahonen, Y Guo, LF Lu, D Gondek, Y Wang, RA Fava, A Fiser, S Almo, RJ Noelle: VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. In: J Exp Med.. 208, Nr. 3, 14. März 2011, S. 577–92. PMID 21383057.
J Hendriks, LA Gravestein, K Tesselaar, RA van Lier, TN Schumacher, J Borst: CD27 is required for generation and long-term maintenance of T cell immunity. In: Nat Immunol.. 171, Nr. 5, 1. November 2000, S. 433–40. PMID 11062504.
B O’Sullivan, R Thomas: CD40 and dendritic cell function. In: Crit Rev Immunol.. 23, Nr. 1, 1. Januar 2003, S. 83–107. PMID 12906261.
M Croft, T So, W Duan, P Soroosh: The significance of OX40 and OX40L to T-cell biology and immune disease. In: Immunol Rev.. 229, Nr. 1, 1. Mai 2009, S. 173–191. PMID 19426222.
S Ronchetti, O Zollo, S Bruscoli, M Agostini, R Bianchini, G Nocentini, E Ayroldi, C Riccardi: GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations.. In: Eur J Immunol.. 34, Nr. 3, 1. März 2004, S. 613–22. PMID 14991590.
RS Mittler, J Foell, M McCausland, S Strahotin, L Niu, A Bapat, LB Hewes: Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. In: Immunol Res.. 29, Nr. 1, 1. Juni 2004, S. 197–208. PMID 15181282.
D Eastwood, L Findlay, S Poole, C Bird, M Wadhwa, M Moore, C Burns, R Thorpe, R Stebbings: Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. In: Br J Pharmacol.. 161, Nr. 3, 1. Oktober 2010, S. 512–526. PMID 20880392.
Y Burmeister, T Lischke, AC Dahler, HW Mages, KP Lam, AJ Coyle, RA Kroczek, A Hutloff: ICOS controls the pool size of effector-memory and regulatory T cells. In: J Immunol.. 180, Nr. 2, 15. Januar 2008, S. 774–782. PMID 18178815.

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[1] RD Leone, YC Lo, JD Powell: A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. In: Comput Struct Biotechnol J.. 13, 8. April 2015, S. 265–. PMID 25941561.

[2] AI Chapoval, J Ni, JS Lau, RA Wilcox, DB Flies, D Liu, H Dong, GL Sica, G Zhu, K Tamada, L Chen: B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. In: Nat Immunol.. 2, Nr. 3, 1. März 2001, S. 269–74. PMID 11224528.

[3] J Leitner, C Klauser, WF Pickl, J Stöckl, O Majdic, AF Bardet, DP Kreil, C Dong, T Yamazaki, G Zlabinger, K Pfistershammer, P Steinberger: B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. In: Eur J Immunol.. 39, Nr. 7, 1. Juli 2009, S. 1754–64. PMID 19544488.

[4] L Derré, JP Rivals, C Jandus, S Pastor, D Rimoldi, P Romero, O Michielin, D Olive, DE Speiser: BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. In: J Clin Invest.. 120, Nr. 1, 1. Januar 2010, S. 157–67. PMID 20038811.

[5] P Kolar, K Knieke, JK Hegel, D Quandt, GR Burmester, H Hoff, Brunner-Weinzierl MC: CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. In: Arthritis Rheum.. 60, Nr. 1, 1. Januar 2009, S. 123–32. PMID 19116935.

[6] GC Prendergast, C Smith, S Thomas, Mandik-Nayak L, Laury-Kleintop L, R Metz, AJ Muller: Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. In: Cancer Immunol Immunother.. 63, Nr. 7, 1. Juli 2014, S. 721–35. PMID 24711084.

[7] CT Huang, CJ Workman, D Flies, X Pan, AL Marson, G Zhou, EL Hipkiss, S Ravi, J Kowalski, HI Levitsky, JD Powell, DM Pardoll, CG Drake, DA Vignali: Role of LAG-3 in regulatory T cells. In: Immunity.. 21, Nr. 4, 1. Oktober 2004, S. :503–13. PMID 15485628.

[8] GK Philips, M Atkins: Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. In: Int Immunol.. 27, Nr. 1, 1. Januar 2015, S. 39–46. PMID 25323844.

[9] WD Hastings, DE Anderson, N Kassam, K Koguchi, EA Greenfield, SC Kent, XX Zheng, TB Strom, DA Hafler, VK Kuchroo: TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. In: Eur J Immunol.. 39, Nr. 9, 1. September 2009, S. 2492–501. PMID 19676072.

[10] L Wang, R Rubinstein, JL Lines, A Wasiuk, C Ahonen, Y Guo, LF Lu, D Gondek, Y Wang, RA Fava, A Fiser, S Almo, RJ Noelle: VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. In: J Exp Med.. 208, Nr. 3, 14. März 2011, S. 577–92. PMID 21383057.

[11] J Hendriks, LA Gravestein, K Tesselaar, RA van Lier, TN Schumacher, J Borst: CD27 is required for generation and long-term maintenance of T cell immunity. In: Nat Immunol.. 171, Nr. 5, 1. November 2000, S. 433–40. PMID 11062504.

[12] B O’Sullivan, R Thomas: CD40 and dendritic cell function. In: Crit Rev Immunol.. 23, Nr. 1, 1. Januar 2003, S. 83–107. PMID 12906261.

[13] M Croft, T So, W Duan, P Soroosh: The significance of OX40 and OX40L to T-cell biology and immune disease. In: Immunol Rev.. 229, Nr. 1, 1. Mai 2009, S. 173–191. PMID 19426222.

[14] S Ronchetti, O Zollo, S Bruscoli, M Agostini, R Bianchini, G Nocentini, E Ayroldi, C Riccardi: GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations.. In: Eur J Immunol.. 34, Nr. 3, 1. März 2004, S. 613–22. PMID 14991590.

[15] RS Mittler, J Foell, M McCausland, S Strahotin, L Niu, A Bapat, LB Hewes: Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. In: Immunol Res.. 29, Nr. 1, 1. Juni 2004, S. 197–208. PMID 15181282.

[16] D Eastwood, L Findlay, S Poole, C Bird, M Wadhwa, M Moore, C Burns, R Thorpe, R Stebbings: Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. In: Br J Pharmacol.. 161, Nr. 3, 1. Oktober 2010, S. 512–526. PMID 20880392.

[17] Y Burmeister, T Lischke, AC Dahler, HW Mages, KP Lam, AJ Coyle, RA Kroczek, A Hutloff: ICOS controls the pool size of effector-memory and regulatory T cells. In: J Immunol.. 180, Nr. 2, 15. Januar 2008, S. 774–782. PMID 18178815.