Escape Strategies of Tumors from Immune Surveillence
Authors:
M. Šťastný 1*; B. Říhová 2**
Authors place of work:
Bristol‑ Myers Squibb spol. s r. o., Praha2 Mikrobiologický ústav AV ČR, v. v. i., Praha
1
Published in the journal:
Klin Onkol 2015; 28(Supplementum 4): 28-37
Category:
Generals
doi:
https://doi.org/10.14735/amko20154S28
Summary
Immune system must be able to protect us from foreign dangerous pathogens, but on the other side, it must be able to recognize our own tissues and organs. Activity of the immune system is affected by many positive (stimulatory) and negative (inhibitory) signals. Some of these negative receptors protect us from damage of our tissues at a place of inflammation as it blocks too intensive or long‑lasting immune reaction. Thereby, they have a physiological protective function against strong inflammatory reaction and possible subsequent autoimmune pathology. However, some of these mechanisms are also utilized by tumors to avoid immune recognition and attention of the immune cells. Other tumor escape mechanisms involve increased production of cytokines and factors which are responsible for immunosuppressive tumor microenvironment where effective immune response is actively blocked. This review summarizes the most frequently used strategies, which are utilized by tumors to avoid immune recognition and/ or killing by the immune cells.
Key words:
immune evasion – tumor escape – immunotherapy – CTLA-4 – PD-1 – immune checkpoint
* I declare that, in connection with this contribution of which I am the co-author, I have a conflict of interest with following company: Bristol-Myers Squibb al. s r. o.
Author is former employee of Institute of Microbiology of the AS CR, v. v. i., Prague.
** The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
4. 8. 2015
Accepted:
1. 10. 2015
Zdroje
1. Monge J, Kricun M, Radovčić J et al. Fibrous dysplasia in a 120,000+ year old Neandertal from Krapina, Croatia. PLoS One 2013; 8(6): e64539. doi:10.1371/ journal.pone.0064539.
2. Casanova JL, Abel L. The genetic theory of infectious diseases: a brief history and selected illustrations. Annu Rev Genomics Hum Genet 2013; 14: 215– 243. doi: 10.1146/ annurev genom‑ 091212‑ 153448.
3. Stutman O. Tumor development after 3- methylcholanthrene in immunologically deficient athymic- nude mice. Science 1974; 183(4124): 534– 536.
4. Kaplan DH, Shankaran V, Dighe AS et al. Demonstration of an interferon γ‑ dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 1998; 95(13): 7556– 7561.
5. Shankaran VH, Ikeda A, Bruce T et al. IFNγ, and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410(6832): 1107– 1111.
6. Dunn GP, Bruce AT, Sheehan KC et al. A critical function for type I interferons in cancer immunoediting. Nat Immunol 2005; 6(7): 722– 729.
7. Schreiber RD, Old LJ, Smyth MJ. Suppression and promotion cancer immunoediting: integrating immunity‘s roles in cancer. Science 2011; 331(6024): 1565– 1570. doi: 10.1126/ science.1203486.
8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646– 674. doi: 10.1016/ j.cell.2011.02.013.
9. Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450(7171): 903– 907.
10. Kasiske BL, Snyder JJ, Gilbertson DT et al. Cancer after kidney transplantation in the United States. Am J Transplant 2004; 4(6): 905– 913.
11. Robbins HA, Pfeiffer RM, Shiels MS et al. Excess cancers among HIV‑ infected people in the United States. J Natl Cancer Inst 2015; 107(4). pii: dju503. doi: 10.1093/ jnci/ dju503.
12. MacKie RM, Reid R, Junor B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 2003; 348(6): 567– 568.
13. Cozar JM, Aptsiauri N, Tallada M et al. Late pulmonary metastases of rena cell carcinoma immediately after post‑transplantation immunosuppressive treatment: a case report. J Med Case Rep 2008; 2: 111. doi: 10.1186/ 1752‑ 1947‑ 2‑ 111.
14. Meng S, Tripathy D, Frenkel EP et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004; 10(24): 8152– 8162.
15. Melichar B, Vanecková J, Morávek P et al. Spontaneous regression of renal cell carcinoma lung metastases in a patient with psoriasis. Acta Oncol 2009; 48(6): 925– 927. doi: 10.1080/ 02841860902882451.
16. Jäger E, Ringhoffer M, Altmannsberger M et al. Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 1997; 71(2): 142– 147.
17. Driessens G, Kline J, Gajewski TF. Costimulatory and coinhibitory receptors in anti‑tumor immunity. Immunol Rev 2009; 229(1): 126– 144. doi: 10.1111/ j.1600‑ 065X.2009.00771.x.
18. Peggs KS, Quezada SA, Korman AJ et al. Principles and use of anti‑CTLA4 antibody in human cancer. Curr Opin Immunol 2006; 18(2): 206– 213.
19. Nurieva RI, Liu X, Dong C. Yin‑Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev 2009; 229(1): 88– 100. doi: 10.1111/ j.1600‑ 065X.2009.00769.x.
20. Peggs KS, Quezada SA, Allison JP. Cancer immunotherapy: co‑ stimulatory agonists and co‑inhibitory antagonists. Clin Exp Immunol 2009; 157(1): 9– 19. doi: 10.1111/ j.1365‑ 2249.2009.03912.x.
21. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol 2012; 13(12): 1129– 1132. doi: 10.1038/ ni.2392.
22. Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993; 11: 191– 212.
23. Jenkins MK, Johnson JG. Molecules involved in T‑ cell costimulation. Curr Opin Immunol 1993; 5(3): 361– 367.
24. Abbas AK, Lichtman AH, Pillai S (eds). Cellular and molecular immunology. 6th ed. Philadelphia, PA: Elsevier Saunders 2010.
25. Moran AE, Kovacsovics‑ Bankowski M, Weinberg AD. The TNFRs OX40, 4- 1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 2013; 25(2): 230– 237. doi: 10.1016/ j.coi.2013.01.004.
26. Perez‑ Gracia JL, Labiano S, Rodriguez‑ Ruiz ME et al. Orchestrating immune check‑ point blockade for cancer immunotherapy in combinations. Curr Opin Immunol 2014; 27: 89– 97. doi: 10.1016/ j.coi.2014.01.002.
27. Krummel MF, CTLA‑ 4 have opposingAllison JP. CD28 and effects on the response of T cells to stimulation. J Exp Med 1995; 182(2): 459– 465.
28. Sharma P, Allison JP. The future of immune check-point therapy. Science 2015; 348 (6230): 56– 61. doi: 10.1126/ science.aaa8172.
29. Tivol EA, Borriello F, Schweitzer AN et al. Loss of CTLA‑ 4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA‑ 4. Immunity 1995; 3(5): 541– 547.
30. Alegre ML, Frauwirth KA, Thompson CB. T‑ cell regulation by CD28 and CTLA‑ 4. Nat Rev Immunol 2001; 1(3): 220– 228.
31. Greenfield EA, Nguyen KA, Kuchroo VK. CD28/ B7 costimulation: a review. Crit Rev Immunol 1998; 18(5): 389– 418.
32. Petrausch U, Poehlein CH, Jensen SM et al. Cancer immunotherapy: the role regulatory T cells play and what can be done to overcome their inhibitory effects. Curr Mol Med 2009; 9(6): 673– 682.
33. Liu VC, Wong LY, Jang T et al. Tumor evasion of the immune system by converting CD4+CD25– T cells into CD4+CD25+ T regulatory cells: role of tumor‑ derived TGF‑beta. J Immunol 2007; 178(5): 2883– 2892.
34. Wing K, Onishi Y, Prieto‑ Martin P et al. CTLA‑ 4 control over Foxp3+ regulatory T cell function. Science 2008; 322(5899): 271– 275. doi: 10.1126/ science.1160062.
35. Ishida Y, Agata Y, Shibahara K et al. Induced expression of PD‑ 1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11(11): 3887– 3895.
36. Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439(7077): 682– 687.
37. Day CL, Kaufmann DE, Kiepiela P et al. PD‑ 1 expression on HIV‑ specific T cells is associated with T‑ cell exhaustion and disease progression. Nature 2006; 443(7109): 350– 354.
38. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA‑ 4 and PD‑ 1 blockade as cancer immunotherapy. J Leukoc Biol 2013; 94(1): 25– 39. doi: 10.1189/ jlb.1212621.
39. Nishimura H, Okazaki T, Tanaka Y et al. Autoimmune dilated cardiomyopathy in PD‑ 1 receptor‑ deficient mice. Science 2001; 291(5502): 319– 322.
40. Okazaki T, Tanaka Y, Nishio R et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD‑ 1-deficient mice. Nat Med 2003; 9(12): 1477– 1483.
41. Keir ME, Butte MJ, Freeman GJ et al. PD‑ 1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677– 704. doi: 10.1146/ annurev.immunol.26.021607.090331.
42. Blank C, Mackensen A. Contribution of the PD‑ L1/ PD‑ 1 pathway to T‑ cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 2007; 56(5): 739– 745.
43. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer – preclinical background: CTLA‑ 4 and PD‑ 1 blockade. Semin Oncol 2010; 37(5): 430– 439. doi: 10.1053/ j.seminoncol.2010.09.005.
44. Hirano F, Kaneko K, Tamura H et al. Blockade of B7- H1 and PD‑ 1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005; 65(3): 1089– 1096.
45. Nomi T, Sho M, Akahori T et al. Clinical significance and therapeutic potential of the programmed death‑ 1 ligand/ programmed death‑ 1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13(7): 2151– 2157.
46. Peng W, Liu C, Xu C et al. PD‑ 1 blockade enhances T‑ cell migration to tumors by elevating IFN‑ gamma inducible chemokines. Cancer Res 2012; 72(20): 5209– 5218. doi: 10.1158/ 0008‑ 5472.CAN‑ 12‑ 1187.
47. Iwai Y, Terawaki S, Honjo T. PD‑ 1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol 2005; 17(2): 133– 144.
48. Shi F, Shi M, Zeng Z et al. PD‑ 1 and PD‑ L1 upregulation promotes CD8(+) T‑ cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011; 128(4): 887– 896. doi: 10.1002/ ijc.25397.
49. Hino R, Kabashima K, Kato Y et al. Tumor cell expression of programmed cell death‑ 1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010; 116(7): 1757– 1766. doi: 10.1002/ cncr.24899.
50. Richendollar BG, Pohlman B, Elson P et al. Follicular programmed death 1- positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma. Human Pathol 2011; 42(4): 552– 527. doi: 10.1016/ j.humpath.2010.08.015.
51. Dorfman DM, Brown JA, Shahsafaei A et al. Programmed death‑ 1 (PD‑ 1) is a marker of germinal center‑associated T-cells and angioimmunoblastic T‑ cell lymphoma. Am J Surg Pathol 2006; 30(7): 802– 810.
52. Liu J, Hamrouni A, Wolowiec D et al. Plasma cells from multiple myeloma patients express B7- H1 (PD‑ L1) and increase expression after stimulation with IFN‑ {gamma} and TLR ligands via a MyD88- , TRAF6- , and MEK‑ dependent pathway. Blood 2007; 110(1): 296– 304.
53. Iwai Y, Ishida M, Tanaka Y et al. Involvement of PD‑ L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD‑ L1 blockade. Proc Natl Acad Sci USA 2002; 99(19): 12293– 12297.
54. Hamanishi J, Mandai M, Iwasaki M et al. Programmed cell death 1 ligand 1 and tumor‑ infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007; 104(9): 3360– 3365.
55. Ishikawa T, Fujita T, Suzuki Y et al. Tumor‑ specific immunological recognition of frameshift‑ mutated peptides in colon cancer with microsatellite instability. Cancer Res 2003; 63(7): 5564– 5572.
56. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369(2): 122– 133. doi: 10.1056/ NEJMoa1302369.
57. Herbst RS, Soria JC, Kowanetz M et al. Predictive correlates of response to the anti‑PD‑ L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563– 567. doi: 10.1038/ nature14011.
58. Robert C, Ribas A, Wolchok JD et al. Anti‑programmed‑ death‑ receptor‑ 1 treatment with pembrolizumab in ipilimumab‑ refractory advanced melanoma: a randomized dose‑comparison cohort of a phase 1 trial. Lancet 2014; 384(9948): 1109– 1117. doi: 10.1016/ S0140‑ 6736(14)60958‑ 2.
59. Weber JS, D‘Angelo SP, Minor D et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti‑CTLA‑ 4 treatment (CheckMate 037): a randomized, controlled, open‑ label, phase 3 trial. Lancet Oncol 2015; 16(4): 375– 384. doi: 10.1016/ S1470‑ 2045(15)70076‑ 8.
60. Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320– 330. doi: 10.1056/ NEJMoa1412082.
61. Larkin J, Chiarion‑ Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23– 34. doi: 10.1056/ NEJMoa1504030.
62. Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372(21): 2006– 2017. doi: 10.1056/ NEJMoa1414428.
63. Rizvi NA, Hellmann MD, Snyder A et al. Cancer immunology. Mutational landscape determines sensitivity to PD‑ 1 blockade in non‑small cell lung cancer. Science 2015; 348(6230): 124– 128. doi: 10.1126/ science.aaa1348.
64. Rizvi NA, Mazières J, Planchard D et al. Activity and safety of nivolumab, an anti‑PD‑ 1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non‑small‑cell lung cancer (CheckMate 063): a phase 2, single‑arm trial. Lancet Oncol 2015; 16(3): 257– 265. doi: 10.1016/ S1470‑ 2045(15)70054‑ 9.
65. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous‑ cell non‑small‑cell lung cancer. N Engl J Med 2015; 373(2): 123– 135. doi: 10.1056/ NEJMoa1504627.
66. Gettinger SN, Horn L, Gandhi L et al. Overall survival and long‑term safety of nivolumab (anti‑programmed death 1 antibody, BMS‑ 936558, ONO‑ 4538) in patients with previously treated advanced non‑small‑cell lung cancer. J Clin Oncol 2015; 33(18): 2004– 2012. doi: 10.1200/ JCO.2014.58.3708.
67. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non‑small‑cell lung cancer. N Engl J Med 2015; 372(21): 2018– 2028. doi: 10.1056/ NEJMoa1501824.
68. Sierro S, Romero P, Speiser DE. The CD4‑like molecule LAG‑ 3, biology and therapeutic applications. Expert Opin Ther Targets 2011; 15(1): 91– 101. doi: 10.1517/ 14712598.2011.540563.
69. Goldberg MV, Drake CG. LAG‑ 3 in cancer immunotherapy. Curr Top Microbiol Immunol 2011; 344: 269– 278. doi: 10.1007/ 82_2010_114.
70. Grosso JF, Kelleher CC, Harris TJ et al. LAG‑ 3 regulates CD8+ T cell accumulation and effector function in murine self‑ and tumor‑ tolerance systems. J Clin Invest 2007; 117(11): 3383– 3392.
71. Woo SR, Turnis ME, Goldberg MV et al. Immune inhibitory molecules LAG‑ 3 and PD‑ 1 synergistically regulate T‑ cell function to promote tumoral immune escape. Cancer Res 2012; 72(4): 917– 927. doi: 10.1158/ 0008‑ 5472.CAN‑ 11‑ 1620.
72. Zhu C, Anderson AC, Schubart A et al. The Tim 3 ligand galectin 9 negatively regulates T helper type 1 immunity. Nature Immunol 2005; 6(12): 1245– 1252.
73. Ngiow SF, von Scheidt B, Akiba H et al. Anti TIM3 antibody promotes T cell IFN γ‑ mediated antitumor immunity and suppresses established tumors. Cancer Res 2011; 71(10): 3540– 3551. doi: 10.1158/ 0008‑ 5472.CAN‑ 11‑ 0096.
74. Sakuishi K, Apetoh L, Sullivan JM et al. Targeting Tim 3and PD 1 pathways to reverse T cell exhaustion and restore anti‑tumor immunity. J Exp Med 2010; 207(10): 2187– 2194. doi: 10.1084/ jem.20100643.
75. Gao X, Zhu Y, Li G et al. TIM‑ 3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 2012; 7(2): e30676. doi: 10.1371/ journal.pone.0030676.
76. Partlová S, Bouček J, Kloudová K et al. Distinct patterns of intratumoral immune cell infiltrates in patients with HPV‑associated compared to non‑virally induced head and neck squamous cell carcinoma. Oncoimmunology 2015; 4(1): e965570.
77. Uyttenhove L, Pilotte I, 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.
78. Pilotte L, Larrieu P, Stroobant V et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3- dioxygenase. Proct Natl Acad Sci U S A 2012; 109(7): 2497– 2502. doi: 10.1073/ pnas.1113873109.
79. Tanizaki Y, Kobayashi A, Toujima S et al. Indoleamine 2,3- dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. Cancer Sci 2014; 105(8): 966– 973. doi: 10.1111/ cas.12445.
80. Jiang T, Sun Y, Yin Z et al. Research progress of indoleamine 2,3- dioxygenase inhibitors. Future Med Chem 2015; 7(2): 185– 201. doi: 10.4155/ fmc.14.151.
81. Saraiva M, O‘Garra A. The regulation of IL‑10 production by immune cells. Nat Rev Immunol 2010; 10(3): 170– 181. doi: 10.1038/ nri2711.
82. Mannino MH, Zhu Z, Xiao H et al. The paradoxical role of IL‑10 in immunity and cancer. Cancer Lett 2015; 367(2): 103– 107. doi: 10.1016/ j.canlet.2015.07.009.
83. Massague J. TGFbeta in Cancer. Cell 2008; 134(2): 215– 230. doi: 10.1016/ j.cell.2008.07.001.
84. Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol 2005; 23(9): 2078– 2093.
85. Kehrl JH, Wakefield LM, Roberts AB et al. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 1986; 163(5): 1037– 1050.
86. Shull MM, Ormsby I, Kier AB et al. Targeted disruption of the mouse transforming growth factor‑beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359(6397): 693– 699.
87. Tu E, Chia PZ, Chen W. TGFβ in T cell biology and tumor imunity: angel or devil? Cytokine Growth Factor Rev 2014; 25(4): 423– 435. doi: 10.1016/ j.cytogfr.2014.07.014.
88. Kretschmer K, Apostolou I, Jaeckel E et al. Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunol Rev 2006; 212: 163– 169.
89. Fridman WH, Pagès F, Sautès‑ Fridman C et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012; 12(4): 298– 306. doi: 10.1038/ nrc3245.
90. Italiani P, Boraschi D. From monocytes to M1/ M2 macrophages: phenotypical vs. functional differentiation. Front Immunol 2014; 5: 514. doi: 10.3389/ fimmu.2014.00514.
91. Galdiero MR, Garlanda C, Jaillon S et al. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 2013; 228(7): 1404– 1412. doi: 10.1002/ jcp.24260.
92. Parker KH, Beury DW, Ostrand‑ Rosenberg S. Myeloid‑ derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 2015; 128: 95– 139. doi: 10.1016/ bs.acr.2015.04.002.
93. Cohen PL, Eisenberg RA. The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunol Today 1992; 13(11): 427– 428.
94. Owen‑ Schaub L, Chan H, Cusack JC et al. Fas and Fas ligand interactions in malignant disease. Int J Oncol 2000; 17(1): 5– 12.
95. Igney FH, Behrens CK, Krammer PH. Tumor counterattack‑ concept and reality. Eur J Immunol 2000; 30(3): 725– 731.
96. Motz GT, Santoro SP, Wang LP et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014; 20(6): 607– 615. doi: 10.1038/ nm.3541.
97. Couzin‑Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013; 342(6165): 1432– 1433. doi: 10.1126/science.342.6165.1432.
Štítky
Paediatric clinical oncology Surgery Clinical oncologyČlánok vyšiel v časopise
Clinical Oncology
2015 Číslo Supplementum 4
- Metamizole at a Glance and in Practice – Effective Non-Opioid Analgesic for All Ages
- Metamizole vs. Tramadol in Postoperative Analgesia
- Spasmolytic Effect of Metamizole
- Possibilities of Using Metamizole in the Treatment of Acute Primary Headaches
- Current Insights into the Antispasmodic and Analgesic Effects of Metamizole on the Gastrointestinal Tract
Najčítanejšie v tomto čísle
- Side‑ effects of Modern Immunotherapy and How to Solve Them in the Clinics
- Immunotherapy of Urothelial Carcinoma of the Bladder – from BCG Vaccines to Targeted Therapy
- Escape Strategies of Tumors from Immune Surveillence
- The Concept of Immunogenic Cell Death in Antitumor Immunity