Tumorigenesis as an autoimmune process
https://doi.org/10.15789/1563-0625-TAA-3152
Abstract
The data presented in the article reasonably indicate that the immune system responses during the development of autoimmune pathology and in the process of tumor growth are, in fact, autoimmune responses directed at autoantigens of various tissues and organs, and tumor-associated antigens. The latter, in addition to the tumor itself, are also expressed by the cells of normal organs and tissues. At the same time, the differences are characterized by insufficient activity of suppressor cells in the first variant, and enhanced activity in the second variant. One should take into account a potential identity of the mechanisms of lymphocyte responses, both in autoimmune pathology and in oncogenesis. The concept of autoimmunity promoting the tumor development is a fundamentally important point, with regard of the tumor growth biology. In view of medicine, this approach may provide a vector for searching novel drug effects aimed at inhibiting the suppressor activity of regulatory cells, without higher risk of inducing autoimmune disorders. On the basis of available literature data, one may suggest that the formation of autoimmune pathology is caused by the impaired mechanisms of immune tolerance to autoantigens. Moreover, these mechanisms concern both central tolerance and peripheral tolerance. In the first case, T cells bearing high-affinity receptors directed against autoantigens are not subject to negative selection in the thymus and migrate to the periphery, being ready to induce autoimmune processes. At the same time, peripheral T regulatory suppressor cells do not work with respect to suppression of their activity. There is an evident disturbance of the both central and peripheral tolerance mechanisms. In the case of tumor growth, it has been shown that suppression of T regulatory cells results in development of autoimmune pathology, along with inhibition of tumor growth. The recent data from the literature allow us to suggest a targeted reaction of immune cells against tumor-associated antigens, and not against tumor-specific antigens. One should assume that these T cell effectors against tumor-associated antigens also have reached the peripheral tissues after migration from the thymus, without undergoing negative selection. However, their antitumor activity on the periphery could be suppressed by T regulatory cells. Apparently, it should be considered that the immune response to tumor growth exhibited features of an autoimmune response to tumor-associated antigens with induction of its activities by means of T regulatory immune cells.
About the Author
V. A. KozlovRussian Federation
Kozlov Vladimir. A., PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Head, Laboratory of Clinical Immunopathology, Scientific Advisor
Novosibirsk
References
1. Ahmadpour S., Habibi M.A., Ghazi F.S., Molazadeh M., Mohammad Pashaie M.R., Mohammadpourf Y. The effects of tumor-derived supernatants (TDS) on cancer cell progression: A review and update on carcinogenesis and immunotherapy. Cancer Treat. Res. Commun., 2024, Vol. 40, 100823. doi: 10.1016/j.ctarc.2024.100823.
2. Berrih-Aknin S., Panse R.L., Dragin N. AIRE: a missing link to explain female susceptibility to autoimmune diseases. Ann. N. Y. Acad. Sci., 2018, Vol. 1412, no. 1, pp. 21-32.
3. Blokzijl F., de Ligt J., Jager M., Sasselli V., Roerink S., Sasaki N., Huch M., Boymans S., Kuijk E., Prins P., Nijman I.J., Martincorena I., Mokry M., Wiegerinck C.L., Middendorp S., Sato T., Schwank G., Nieuwenhuis E.E., Verstegen M.M., van der Laan L.J., de Jonge J., IJzermans J.N., Vries R.G., van de Wetering M., Stratton M.R., Clevers H., Cuppen E., van Boxtel R. Tissue-specific mutation accumulation in human adult stem cells during life. Nature, 2016, Vol. 538, pp. 260-264.
4. Castellano D., Sepulvera J.M., Garcia-Escobar I., Rodrigues-Antolin A., Sundlo V.A., Cortes-Funes C. The Role of RANK-ligand inhibition in cancer: the story of denosumab. Oncologist, 2011, Vol. 16, pp. 136-145.
5. de Groot A.F., Appelman-Dijkstra N.M., van der Burg S.H., Kroep J.R. The anti-tumor effect of RANKL inhibition in malignant solid tumors – A systematic review. Cancer Treat. Rev., 2018, Vol. 62, pp. 18-28.
6. Dummer W., Niethammer A.G., Baccala R., Lawson B.R., Wagner N., Reisfeld R.A., Theofilopoulo A.N. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J. Clin. Invest., 2002, Vol. 110, pp. 185-192.
7. Dunn G.P., Bruce A.T., Ikeda H., Old L.J., Schreiber R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol., 2002, Vol. 3, no. 11, pp. 991-998.
8. Ernst B., Lee D.S., Chang J.M., Sprent J., Surh C.D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in periphery. Immunity, 1999, Vol. 11, pp. 173-181.
9. Fane M., Weeraratna A.T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer, 2020, Vol. 20, no. 2, pp. 89-106.
10. Fink P.J. The biology of recent thymic emigrants. Annu. Rev. Immunol., 2013, Vol. 31, pp. 31-50.
11. Franks A.L., Slansky J.E. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res., 2012, Vol. 329, no. 4, pp. 1119-1136.
12. Friesen T.J., Ji Q., Fink P.J. Recent thymic emigrants are tolerized in the absence of inflammation. J. Exp. Med., 2016, Vol. 213, no. 6, pp. 913-920.
13. Gill J., Malin M., Sutherland J., Gray D., Hollander G., Boyd R. Thymic generation and regeneration. Immunol. Rev., 2003, Vol. 195, pp. 28-50.
14. Gogas H., Ioannovich J., Dafni U., Stavropoulou-Giokas C., Frangia K., Tsoutsos D., Panagiotou P., Polyzos A., Papadopoulos O., Stratigos A., Markopoulos C., Bafaloukos D., Pectasides D., Fountzilas G., Kirkwood J.M. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N. Engl. J. Med., 2006, Vol. 354, no. 7, pp. 709-718.
15. Gravano D.M., Vignali D.A. The battle against immunopathology: infectious tolerance mediated by regulatory T cells. Cell. Mol. Life Sci., 2012, Vol. 69, no. 12, pp. 1997-2008.
16. Gui J.G., Mustachio L.M., Su D M., Craig R.W. Thymus size and age-related thymic involution: Early programming, sexual dimorphism, progenitors and stroma. Aging Dis., 2012, Vol 3, no. 3, pp. 280-290.
17. Hadeiba H., Butcher E.C. Thymus-homing dendritic cells in central tolerance. Eur. J. Immunol., 2013, Vol. 43, no. 6, pp. 1425-1429.
18. Hun M.L., Wong K., Gunawan J.R., Alsharif A., Quinn, K., Chidgey A.P. Gender disparity impacts on thymus aging and LHRH receptor antagonist-induced thymic reconstitution following chemotherapeutic damage. Front. Immunol., 2020, Vol. 11, 302. doi: 10.3389/fimmu.2020.00302.
19. Kennedy C., Bhatia S., Thompson J.A., Grivas P. Preexisting autoimmune disease: implications for immune checkpoint inhibitor therapy in solid tumors. J. Natl. Compr. Canc. Netw., 2019, Vol. 17, no. 6, pp. 750-757.
20. Khan I.S., Mouchess M.L., Zhu M.L., Conley B., Fasano K.J., Hou Y., Fong L., Su M.A., Anderson M.S. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J. Exp. Med., 2014, Vol. 211, no. 5, pp. 761-768.
21. Kieper W.C., Troy A., Burghardt J.T., Ramsey C., Lee J.Y., Jiang H.Q., Dummer W., Shen H., Cebra J.J., Surh C.D. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol., 2005, Vol. 174, no. 6, pp. 3158-3163.
22. Kumara P., Bhattacharyaa P., Prabhakar B.S. A comprehensive review on the role of co-signaling receptors and treg homeostasis in autoimmunity and tumor immunity. J. Autoimmun., 2018, Vol. 95, pp. 77-99.
23. Liang Z., Dong X., Zhang Z., Zhang Q., Zhao Y. Age-related thymic involution: Mechanisms and functional impact. Aging Cell, 2022, Vol. 21, no. 8, e13671. doi: 10.1111/acel.13671.
24. Millington O.R., Mowat A.M., Garside P. Induction of bystander suppression by feeding antigen occurs despite normal clonal expansion of the bystander T cell population. J. Immunol., 2004, Vol. 173, no. 10, pp. 6059-6064.
25. Mittal D., Gubin M.M., Schreiber R.D., Smyth M.J. New insights into cancer immunoediting and its three component phases – elimination, equilibrium and escape. Curr. Opin. Immunol., 2014, Vol. 27, pp. 16-25.
26. Moses C.T., Thorstenson K.M., Jameson S.C., Khoruts A. Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells. Proc. Natl. Acad. Sci. USA, 2003, Vol. 100, pp. 1185-1190.
27. Overwijk W.W., Theore M.R., Finkelstein S.E., Surman D.R., de Jong L.A., Vyth-Dreese F.V., Dellemijn T.A., Antony P.A., Spiess P.J., Palmer D.C., Heimann D.M., Klebanoff C.A., Yu Z., Hwang L.N., Feigenbaum L., Kruisbeek A.M., Rosenberg S.A., Restifo N.P. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8 T сells. J. Exp. Med., 2003, Vol. 198, no. 4, pp. 569-580.
28. Qi Y., Zhang R., Lu Y., Zou X., Yang W. Aire and Fezf2, two regulators in medullary thymic epithelial cells, control autoimmune diseases by regulating TSAs: Partner or complementer? Front. Immunol., 2022, Vol. 13, 948259. doi: 10.3389/fimmu.2022.948259.
29. Sarter K., Leimgruber E., Gobet F., Agrawal V., Dunand-Sauthier I., Barras E., Mastelic-Gavillet B., Kamath A., Fontannaz P., Guéry L., Duraes F.V., Lippens C., Ravn U., Santiago-Raber M.L., Magistrelli G., Fischer N., Siegrist C.A., Hugues S., Reith W. Btn2a2, a T cell immunomodulatory molecule coregulated with mhc class II genes. J. Exp. Med., 2016, Vol. 213, pp. 177-187.
30. Sheu T.T., Chiang B.L. Lymphopenia, lymphopenia-induced proliferation, and autoimmunity. Int. J. Mol. Sci., 2021, Vol. 22, no. 8, 4152. doi:10.3390/ijms22084152
31. Shevach E.M., Thornton A.M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev., 2014, Vol. 259, no. 1, pp. 88-102.
32. Speiser D.E., Miranda R., Zakarian A., Bachmann M.F., McKall-Faienza K., Odermatt B., Hanahan D., Zinkernagel R.F., Ohashi P.S. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J. Exp. Med., 1997, Vol. 186, no. 5, pp. 645-653.
33. Stanworth R.D., Jones T.H. Testosterone for the aging male; current evidence and recommended practice. Clin. Interv. Aging, 2008, Vol. 3, no. 1, pp. 25-44.
34. Stone J.D., Harris D.T., Kranz D.M. TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity. Curr. Opin. Immunol., 2015, Vol. 33, pp. 16-22.
35. Su M.A., Anderson M.S. Pulling RANK on cancer: blocking Aire-mediated central tolerance to enhance immunotherapy. Cancer Immunol. Res., 2019, Vol. 7, pp. 854-859.
36. Tajima M., Wakita D., Noguchi D., Chamoto K., Yue Z., Fugo K., Ishigame H., Iwakura Y., Kitamura H., Nishimura T. IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells. J. Exp. Med., 2008, Vol. 205, pp. 1019-1027.
37. Takaba H., Takayanagi H. The mechanisms of T cell selection in the thymus. Trends Immunol., 2017, Vol. 38, no. 11, pp. 805-816.
38. Tan J.T., Dudl E., LeRoy E., Murray R., Sprent J., Weinberg K.I., Surh C.D. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA, 2001, Vol. 98, pp. 8732-8737.
39. Tomofuji Y., Takaba H., Suzuki H.I., Benlaribi R., Martinez C.D.P., Abe Y., Morishita Y., Okamura T., Taguchi A., Kodama T., Takayanagi H. Chd4 choreographs self-antigen expression for central immune tolerance. Nat. Immunol., 2020, Vol. 8, pp. 892-901.
40. Tuncel J., Holmberg J., Haag S., Hopkins M.H., Wester-Rosenlöf L., Carlsen S., Olofsson P., Holmdahl R. Self-reactive T cells induce and perpetuate chronic relapsing arthritis.Arthritis Res. Ther., 2020, Vol. 22, no. 1, 95. doi: 10.1186/s13075-020-2104-7.
41. van den Broek T., Borghans J.A.M., van Wijk F. The full spectrum of human naive T cells. Nat. Rev. Immunology, 2018, Vol. 18, no. 6, pp. 363-373.
42. Wang Y., Dong C., Han Y., Gu Z., Chi Sun C. Immunosenescence, aging and successful aging. Front. Immunol., 2022, Vol. 13, 942796. doi: 10.3389/fimmu.2022.942796.
43. Zdrojewicz Z., Pachura E., Pachura P. The thymus: a forgotten, but very important organ. Adv. Clin. Exp. Med., 2016, Vol. 25, no. 2, pp. 369-375.
44. Zhu M.L., Bakhru P., Conley B., Nelson J.S., Free M., Martin A., Starmer J., Wilson E.M., Su M.A. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun., 2016, Vol. 7, 11350. doi: 10.1038/ncomms11350.
45. Zúñiga-Pflücker J.C. The original intrathymic progenitor from which T cells originate. J. Immunol., 2009, Vol. 183, no. 1, pp. 3-4.
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For citations:
Kozlov V.A. Tumorigenesis as an autoimmune process. Medical Immunology (Russia). 2025;27(4):703-712. (In Russ.) https://doi.org/10.15789/1563-0625-TAA-3152