Autoimmune T-cells induced by low dose immune checkpoint blockade could be a powerful therapeutic tool in cancer through activation of eliminative inflammation and immunity

Tibor Bakacs, Katalin Kristóf, Jitendra N Mehrishi, Tamas Szabados, Csaba Kerepesi, Enikoe Regoes, Gabor Tusnady

Abstract


The immune system has been hypothesized to have evolved to purge nascent selfish host cells, while immune defense against xenogeneic alien pathogens appeared later in evolution. To prevent a natural tendency of tumor development, we proposed that immune surveillance is carried out by a coupled system of complementary T cells and host cells. An ongoing internal dialogue between T cells and host cells keeps T cells alive via stimulation by self-antigens while putting strict limits on variations of host cells by eliminating selfish cells. Convincing evidence for such dialogue, which temporarily activates T cells, emerged from the widespread autoimmune events in 72% of advanced melanoma patients treated with the immune checkpoint blocking ipilimumab. This blockade turned physiologic T cell activation into uncontrolled autoimmunity. We suggest that harnessing the unleashed autoimmune power of T cells would be more rewarding to eliminate cancer than copying infectious vaccination to induce tumor specific immunity.

Keywords


cancer deaths; infectious disease deaths; one-signal T cell model; ipilimumab; harnessing autoimmune T cells; fallacy of tumor immunology

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References


Tauber AI. A tale of two immunologies. In: Grignolio A, ed. Immunology Today: Three Historical Perspectives under Three Theoretical Horizons. Bologna: Bononia University Press; 2010: 15-34.

Rinkevich B. Primitive immune systems: are your ways my ways? Immunol Rev 2004; 198: 25-35.

Szabados T, Bakacs T. Sufficient to recognize self to attack non-self: Blueprint for a one-signal T cell model. Journal of Biological Systems 2011; 19(2): 299-317.

Szabados T, Tusnady G, Kerepesi C, Bakacs T. Computational simulations show that a self-centered immune model is more realistic than conventional nonself-centered models. arXiv 2017; arXiv:1507.00950v1.

Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 2015; 13: 211.

Bakacs T, Mehrishi JN, Moss RW. Ipilimumab (Yervoy) and the TGN1412 catastrophe. Immunobiology 2012; 217(6): 583-9.

Bakacs T, Mehrishi JN, Szabo M, Moss RW. Interesting possibilities to improve the safety and efficacy of ipilimumab (Yervoy). Pharmacol Res 2012; 66(2): 192-7.

Slavin S, Moss RW, Bakacs T. Control of minimal residual cancer by low dose ipilimumab activating autologous anti-tumor immunity. Pharmacol Res 2013.

Bakacs T, Mehrishi JN. Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency. Immunobiology 2014; 220: 624-5.

Gett AV, Hodgkin PD. A cellular calculus for signal integration by T cells. Nat Immunol 2000; 1(3): 239-44.

Marchingo JM, Kan A, Sutherland RM, et al. T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion. Science 2014; 346(6213): 1123-7.

Cohen IR. The cognitive paradigm and the immunological homunculus. Immunol Today 1992; 13(12): 490-4.

Forterre P, Prangishvili D. The major role of viruses in cellular evolution: facts and hypotheses. Curr Opin Virol 2013; 3(5): 558-65.

Witzany G. A perspective on natural genetic engineering and natural genome editing. Introduction. Ann N Y Acad Sci 2009; 1178: 1-5.

Martincorena I, Campbell PJ. Somatic mutation in cancer and normal cells. Science 2015; 349(6255): 1483-9.

Klein G. Toward a genetics of cancer resistance. Proceedings of the National Academy of Sciences 2009; 106(3): 859-63.

Friberg S, Mattson S. On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 1997; 65(4): 284-97.

de Magalhaes JP. How ageing processes influence cancer. Nat Rev Cancer 2013; 13(5): 357-65.

Beerenwinkel N, Schwarz RF, Gerstung M, Markowetz F. Cancer evolution: mathematical models and computational inference. Syst Biol 2015; 64(1): e1-25.

Udagawa T. Tumor dormancy of primary and secondary cancers. APMIS 2008; 116(7-8): 615-28.

Guidotti LG, Chisari FV. To kill or to cure: options in host defense against viral infection. Curr Opin Immunol 1996; 8(4): 478-83.

Kristensen VN. The Antigenicity of the Tumor Cell - Context Matters. NEnglJMed 2017; 376(5).

Medzhitov R, Janeway CA, Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91(3): 295-8.

Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 2003; 21: 807-39.

Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol 2015; 33(17): 1974-82.

Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol 2011; 29(36): 4828-36.

Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017; 541(7637): 321-30.

Cohen IR. Activation of benign autoimmunity as both tumor and autoimmune disease immunotherapy: a comprehensive review. J Autoimmun 2014; 54: 112-7.




DOI: http://dx.doi.org/10.18103/imr.v3i4.408

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