Immune Checkpoint Inhibitors: Ctla-4 and Pd-1/Pd-l1 in Immunotherapy

Öz

Cancer immunotherapy aims to strengthen the human immune system to combat cancer and is based on the ability of the immune system to detect the finest biochemical differences between cancer and normal cells. Immunotherapy's advantages among conventional methods are specificity to cancer cells, long-term effects and contribution to healing. Tumors use inhibitory receptors, also known as immune control points, to inhibit anti-tumor immune responses. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte-Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1) receptors. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 control point inhibitors have been observed to provide significant benefits to patients of many different types of malignancies. This study aims to examine the scientific studies on the role of CTLA-4 and PD-1 / PD-L1 in cancer therapy and immunotherapy.

Anahtar Kelimeler

• Cancer,immunotherapy,immun checkpoints,CTLA-4,PD-1,PD-L1

İmmün Kontrol Noktası İnhibitörleri Ctla-4 ve Pd-1/Pd-l1’in İmmünoterapideki Yeri

Öz

Kanser immünoterapisi, kanserle mücadelede insan immün sistemini güçlendirmeyi amaçlar ve immün sistemin kanser ile normal hücreler arasındaki en iyi biyokimyasal farklılıkları tespit etme yeteneğine dayanır. İmmünoterapi; özgüllüğü, uzun süreli etkileri ve iyileşmeye olan katkıları sayesinde, kanser tedavisindeki yerini sağlamlaştırmaya devam etmektedir. Tümörler, anti-tümör immün tepkilerini inhibe etmek için bağışıklık kontrol noktaları olarak da bilinen inhibitör reseptörleri kullanır. Birçok kişide immün-baskılamaya, Sitotoksik T-Lenfosit-İlişkili Antijen-4 (CTLA-4) ve Programlanmış Ölüm-1 (PD-1) reseptörleri aracılık eder. CTLA-4 ve/veya PD-1 kontrol noktası inhibitörlerini hedefleyen monoklonal antikor (mAb) temelli terapilerin, birçok farklı malignin türünde, hastalara gözle görülür yararlar sağladığı gözlemlenmiştir. Bu çalışmanın amacı, CTLA-4 ve PD-1/ PD-L1 tedavilerinin kanser tedavisindeki ve immünoterapideki yeri ile ilgili bilimsel çalışmaları incelemektir.

Anahtar Kelimeler

• Kanser,immünoterapi,immün kontrol noktaları,CTLA-4,PD-1,PD-L1

Kaynakça

1. A Shenoy, J. L. (2016). Cancer cells remodel themselves and vasculature to overcome the endothelial barrier. Cancer Lett., 380(2), 534–544. https://doi.org/10.1186/s40945-017-0033-9.Using
2. Apte, S. S., & Parks, W. C. (2015). Metalloproteinases: A parade of functions in matrix biology and an outlook for the future. Matrix Biology, 44–46, 1–6. https://doi.org/10.1016/j.matbio.2015.04.005
3. Aspeslagh, S., Solinas, C., Routy, B., Allard, B., Dupont, F. A., Buisseret, L., … Kok, M. (2018). Immuno-oncology-101: overview of major concepts and translational perspectives. Seminars in Cancer Biology, 52(February), 1–11. https://doi.org/10.1016/j.semcancer.2018.02.005
4. Baxter, E., Windloch, K., Gannon, F., & Lee, J. S. (2014). Epigenetic regulation in cancer progression. Cell and Bioscience, 4(1). https://doi.org/10.1186/2045-3701-4-45
5. Blomberg, O. S., Spagnuolo, L., & de Visser, K. E. (2018). Immune regulation of metastasis: mechanistic insights and therapeutic opportunities. Disease Models & Mechanisms, 11(10), dmm036236. https://doi.org/10.1242/dmm.036236
6. Bourboulia, D., & Stetler-Stevenson, W. G. (2010). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in Cancer Biology, 20(3), 161–168. https://doi.org/10.1016/j.semcancer.2010.05.002
7. Boussiotis, V. A. (2016). Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. The New England Journal of Medicine, 375(18), 1767–1778. https://doi.org/10.1056/NEJMra1514296
8. Campbell, R. (2013). Biyoloji (9th ed.). Istanbul: Palme Yayıncılık.

9. Caroline Bonnans, Jonathan Chou, Z. W. (2014). Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol., 15(12), 786–801. https://doi.org/10.1038/nrm3904.Remodelling
10. Catalano, V., Turdo, A., Di Franco, S., Dieli, F., Todaro, M., & Stassi, G. (2013). Tumor and its microenvironment: A synergistic interplay. Seminars in Cancer Biology, 23(6), 522–532. https://doi.org/10.1016/j.semcancer.2013.08.007
11. Chiarugi, P., & Cirri, P. (2016). Metabolic exchanges within tumor microenvironment. Cancer Letters, 380(1), 272–280. https://doi.org/10.1016/j.canlet.2015.10.027
12. Chowdhury, F., Dunn, S., Mitchell, S., Mellows, T., Ashton-Key, M., & Gray, J. C. (2015). PD-L1 and CD8 + PD1 + lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy. OncoImmunology, 4(10), e1029701. https://doi.org/10.1080/2162402X.2015.1029701
13. Church, S. E., & Galon, J. (2015). Tumor Microenvironment and Immunotherapy: The Whole Picture Is Better Than a Glimpse. Immunity, 43(4), 631–633. https://doi.org/10.1016/j.immuni.2015.10.004
14. Deryugina, E. I., & Quigley, J. P. (2015). Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biology, 44–46, 94–112. https://doi.org/10.1016/j.matbio.2015.04.004
15. Doan, M. V. W. (2017). İmmünoloji (2nd ed.). Istanbul: Nobel Tıp Kitabevleri.
16. Erdogan, B., & Webb, D. J. (2017). Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans., 45(1), 229–236. https://doi.org/10.1042/BST20160387.Cancer-associated
17. Foy, S. P., Mandl, S. J., dela Cruz, T., Cote, J. J., Gordon, E. J., Trent, E., … Rountree, R. B. (2016). Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells. Cancer Immunology, Immunotherapy, 65(5), 537–549. https://doi.org/10.1007/s00262-016-1816-7
18. Gibney, G. T., Weiner, P. L. M., Atkins, P. M. B., & Comprehensive, L. (2016). Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol., 17(12), 542–551. https://doi.org/10.1016/S1470-2045(16)30406-5.Predictive
19. Hamanishi, J., Mandai, M., Matsumura, N., Abiko, K., Baba, T., & Konishi, I. (2016). PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. International Journal of Clinical Oncology, 21(3), 462–473. https://doi.org/10.1007/s10147-016-0959-z
20. Hirata, E., & Sahai, E. (2017). Tumor Microenvironment and Differential. Cold Spring Harb Perspect Med Doi: https://doi.org/10.1101/cshperspect.a026781
21. Hui, L., & Chen, Y. (2015). Tumor microenvironment: Sanctuary of the devil. Cancer Letters, 368(1), 7–13. https://doi.org/10.1016/j.canlet.2015.07.039
22. Ivey, J. W., Bonakdar, M., Kanitkar, A., Davalos, R. V., & Verbridge, S. S. (2016). Improving cancer therapies by targeting the physical and chemical hallmarks of the tumor microenvironment. Cancer Letters, 380(1), 330–339. https://doi.org/10.1016/j.canlet.2015.12.019
23. Joosse, S. A., Gorges, T. M., & Pantel, K. (2015). Biology, detection, and clinical implications of circulating tumor cells. EMBO Molecular Medicine, 7(1), 1–11. https://doi.org/10.15252/emmm.201303698
24. Kenny, P. A., Lee, G. Y., & Bissell, M. J. (2007). Targeting the tumor microenvironment. Frontiers in Bioscience, 12, 3468–3474.
25. Li, Y., Li, F., Jiang, F., Lv, X., Zhang, R., Lu, A., & Zhang, G. (2016). A mini-review for cancer immunotherapy: Molecular understanding of PD-1/ PD-L1 pathway & translational blockade of immune checkpoints. International Journal of Molecular Sciences, 17(7), 1–22. https://doi.org/10.3390/ijms17071151
26. Lo, B., & Abdel-Motal, U. M. (2017, December 1). Lessons from CTLA-4 deficiency and checkpoint inhibition. Current Opinion in Immunology. Elsevier Ltd. https://doi.org/10.1016/j.coi.2017.07.014
27. Madigan, J. M. M. (2012). Mikroorganizmaların Biyolojisi (11th ed.). Istanbul: Palme Yayıncılık.
28. Majzner, R. G., Simon, J. S., Grosso, J. F., Martinez, D., Pawel, B. R., Santi, M., … Maris, J. M. (2017). Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues. Cancer, 123(19), 3807–3815. https://doi.org/10.1002/cncr.30724
29. Malik, R., Lelkes, P. I., & Cukierman, E. (2015). BIOMECHANICAL and BIOCHEMICAL REMODELING of STROMAL EXTRACELLULAR MATRIX IN CANCER. Trends Biotechnol., 33(4), 230–236. https://doi.org/10.1016/j.tibtech.2015.01.004.BIOMECHANICAL
30. Marcucci, F., Rumio, C., & Corti, A. (2017). Tumor cell-associated immune checkpoint molecules – Drivers of malignancy and stemness. Biochimica et Biophysica Acta - Reviews on Cancer, 1868(2), 571–583. https://doi.org/10.1016/j.bbcan.2017.10.006
31. Masuda, T., Hayashi, N., Iguchi, T., Ito, S., Eguchi, H., & Mimori, K. (2016). Clinical and biological significance of circulating tumor cells in cancer. Molecular Oncology, 10(3), 408–417. https://doi.org/10.1016/j.molonc.2016.01.010
32. Melo, F. H. M. de, Oliveira, J. S., Sartorelli, V. O. B., & Montor, W. R. (2018). Cancer Chemoprevention: Classic and Epigenetic Mechanisms Inhibiting Tumorigenesis. What Have We Learned So Far? Frontiers in Oncology, 8(December), 1–15. https://doi.org/10.3389/fonc.2018.00644
33. Meng, Y., Liang, H., Hu, J., Liu, S., Hao, X., Wong, M. S. K., … Hu, L. (2018). PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer. Journal of Cancer, 9(16), 2938–2945. https://doi.org/10.7150/jca.22532
34. Michael W Pickup, Janna K Mouw, V. M. W. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO Reports, 15, 1243–1253. https://doi.org/10.15252/embr.201439246
35. Missiaen, R., Mazzone, M., & Bergers, G. (2018). The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer. Seminars in Cancer Biology, 52(June), 107–116. https://doi.org/10.1016/j.semcancer.2018.06.002
36. Multhaupt, H. A. B., Leitinger, B., Gullberg, D., & Couchman, J. R. (2016). Extracellular matrix component signaling in cancer. Advanced Drug Delivery Reviews, 97, 28–40. https://doi.org/10.1016/j.addr.2015.10.013
37. Nallasamy, P., Chava, S., Verma, S. S., Mishra, S., Gorantla, S., Coulter, D. W., … Challagundla, K. B. (2018). PD-L1, inflammation, non-coding RNAs, and neuroblastoma: Immuno-oncology perspective. Seminars in Cancer Biology, 52(July 2017), 53–65. https://doi.org/10.1016/j.semcancer.2017.11.009
38. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S., & Honjo, T. (2013). A rheostat for immune responses: The unique properties of PD-1 and their advantages for clinical application. Nature Immunology, 14(12), 1212–1218. https://doi.org/10.1038/ni.2762
39. Ott, P. A., Hodi, F. S., & Robert, C. (2013). CTLA-4 and PD-1/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clinical Cancer Research, 19(19), 5300–5309. https://doi.org/10.1158/1078-0432.CCR-13-0143
40. Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005). Global Cancer Statistics, 2002. CA: A Cancer Journal for Clinicians, 55(2), 74–108. https://doi.org/10.3322/canjclin.55.2.74
41. Potapova T, Zhu J, L. R. (2013). Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev., 32(0). https://doi.org/10.1249/MSS.0000000000000294
42. Rainero, E. (2016). Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer. Biochemical Society Transactions, 44(5), 1347–1354. https://doi.org/10.1042/bst20160159
43. Rangel-Sosa, M. M., Aguilar-Córdova, E., & Rojas-Martínez, A. (2017, September 30). Immunotherapy and gene therapy as novel treatments for cancer. Colombia Medica (Cali, Colombia). https://doi.org/10.25100/cm.v48i3.2997
44. Rejniak, K. A. (2016). Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment. Advances in Experimental Medicine and Biology, 936, 93–106. https://doi.org/10.1007/978-1-4614-1445-2_6
45. Rowshanravan, B., Halliday, N., & Sansom, D. M. (2018, January 4). CTLA-4: A moving target in immunotherapy. Blood. American Society of Hematology. https://doi.org/10.1182/blood-2017-06-741033
46. Shay, G., Lynch, C. C., & Fingleton, B. (2015). Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biology, 44–46, 200–206. https://doi.org/10.1016/j.matbio.2015.01.019
47. Taube, J. M., Galon, J., Sholl, L. M., Rodig, S. J., Cottrell, T. R., Giraldo, N. A., … David, L. (2018). Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol., 31(2), 214–234. https://doi.org/10.1038/modpathol.2017.156.Implications
48. Van Doren, S. R. (2015). Matrix metalloproteinase interactions with collagen and elastin. Matrix Biology, 44–46(i), 224–231. https://doi.org/10.1016/j.matbio.2015.01.005
49. Van Hooren, L., Sandin, L. C., Moskalev, I., Ellmark, P., Dimberg, A., Black, P., … Mangsbo, S. M. (2017). Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer. European Journal of Immunology, 47(2), 385–393. https://doi.org/10.1002/eji.201646583
50. Walker, C., Mojares, E., & del Río Hernández, A. (2018). Role of Extracellular Matrix in Development and Cancer Progression. International Journal of Molecular Sciences (Vol. 19). https://doi.org/10.3390/ijms19103028
51. Walker, L. S. K. (2013, September). Treg and CTLA-4: Two intertwining pathways to immune tolerance. Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2013.06.006
52. Walker, L. S. K., & Sansom, D. M. (2015, February 1). Confusing signals: Recent progress in CTLA-4 biology. Trends in Immunology. Elsevier Ltd. https://doi.org/10.1016/j.it.2014.12.001
53. Wang, L.-H., Wu, C.-F., Rajasekaran, N., & Shin, Y. K. (2018). Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cellular Physiology and Biochemistry, 2647–2693. https://doi.org/10.1159/000495956
54. Weber, C. E., & Kuo, P. C. (2012). The tumor microenvironment. Surgical Oncology, 21(3), 172–177. https://doi.org/10.1016/j.suronc.2011.09.001
55. Wu, T., & Dai, Y. (2017). Tumor microenvironment and therapeutic response. Cancer Letters, 387, 61–68. https://doi.org/10.1016/j.canlet.2016.01.043
56. Yang, L., & Lin, P. C. (2017). Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression. Seminars in Cancer Biology, 47(July), 185–195. https://doi.org/10.1016/j.semcancer.2017.08.001
57. Zhang, X., Wang, C., Wang, J., Hu, Q., Langworthy, B., Ye, Y., Gu, Z. (2018). PD-1 Blockade Cellular Vesicles for Cancer Immunotherapy. Advanced Materials (Deerfield Beach, Fla.), 30(22), e1707112. https://doi.org/10.1002/adma.201707112