RELATIONSHIP OF THE IMMUNOLOGICAL PARAMETRES WITH NEOADJUVANT CHEMOTHERAPY EFFECTIVENESS IN BREAST CANCER PATIENTS
Abstract
Experimental and clinical evidence suggests that the immune system when exposed to conventional cancer chemotherapy is involved in the antitumor effect. A study is conducted to assess the relationship between immunological parameters and effectiveness of neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients. The study included 269 patients with BC (T1–4N0–3M0) and 24 practically healthy comparable age women. The estimation of the subpopulation composition of blood mononuclear cells, their functional activity, apoptosis markers, allelic polymorphism of cytokine genes, depending on the presence or absence of clinical response to NAC was done. Complete tumor regression was associated with an increase in the number of cytotoxic CD8+-cells, high functional activity of lymphocytes (proliferation in response to mitogen, the secretion of cytokines TNFα, IL-1β and IL-10, IFN-γ) and neutrophils. Close relation of highly functional cytokine genotype and high cytokine secretion in blood cells with an objective clinical response to chemotherapy was revealed. Thus, the findings suggest that an objective clinical response to NAC is associated with structural and functional preservation of the immune system. Constitutive characteristics of the patient’s organism, responsible for the level of expression of pathogenetically relevant cytokines that play a key role in the functioning of the immune system are have important meaning.
About the Authors
Y. V. Kukharev
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk
Russian Federation
Russian Federation
M. N. Stakheeva
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk
Russian Federation
Russian Federation
A. V. Doroshenko
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk
Russian Federation
Russian Federation
N. V. Litvyakov
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk
Russian Federation
Russian Federation
N. N. Babyshkina
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk
Russian Federation
Russian Federation
E. M. Slonimskaya
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Siberian State Medical University, Tomsk
Russian Federation
Russian Federation
N. V. Cherdyntseva
Cancer Research Institute Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Siberian State Medical University, Tomsk
Russian Federation
Russian Federation
References
1. Барышников А.Ю., Шишкин Ю.В. Иммунологические проблемы апоптоза. М.: Эдиториал УРСС, 2002. 320 с.
2. Гервас П.А., Литвяков Н.В., Стахеева М.Н. и др. Влияние полиморфизма генов апоптоза и репарации на эффективность неоадъювантной химиотерапии злокачественных новообразований // Сибирский онкологический журнал. 2009. № 4 (34). С. 41–47.
3. Зонова Е.В. Оценка эффективности клинико-иммунологических и иммуногенетических критериев прогноза клинического полиморфизма и терапии ревматоидного артрита: Автореф. дис. … д-ра мед. наук. М., 2010. 55 с.
4. Имангулова М.М., Бикмаева А.Р., Хуснутдинова Э.К. Полиморфизм кластера гена интерлейкина 1 у больных туберкулёзом лёгких // Цитокины и воспаление. 2005. № 1. С. 36–41.
5. Кетлинский С. А., Симбирцев А. С. Цитокины. СПб.: Фолиант, 2008. 552 с.
6. Нестерова И.В., Колесникова Н.В., Симбирцев А.С., Ломатидзе Л.В. Влияние длительного введения синтетического дипептида на функциональную активность нейтрофильных гранулоцитов в эксперименте и in vivo // Иммунология. 1999. № 6. С. 40–43.
7. Никулина Е.Л., Наследникова И.О., Сухаленцева Н.А. и др. Функциональный полиморфизм генов IL10 и TNFA при туберкулёзе лёгких // Материалы XII Российского конгресса молодых ученых с международным участием «Науки о человеке». Томск, 2011. С. 104.
8. Стахеева М.Н., Эйдензон Д., Слонимская Е.М. и др. Взаимосвязь состояния иммунной системы как интегрированного целого с клиническим течением рака молочной железы // Сибирский онкологический журнал. 2011. № 2 (44). C. 11–19.
9. Asadullah K., Sterry W., Volk H.D. Interleukin-10 therapy – review of a new approach // Pharmacol. Rev. 2003. Vol. 55 (2). P. 241–269.
10. Bacacs T., Mehrishi J.N. Breast and other cancer dormancy as a therapeutic endpoint: speculative recombinant T cell receptor ligand (RTL) adjuvant therapy worth considering? // BMC Cancer. 2010. Vol. 10. P. 251–256.
11. Beasley G.M., Olson J.A. Jr. What’s new in neoadjuvant therapy for breast cancer? // Adv. Surg. 2010. Vol. 44. P. 199–228.
12. Chuthapisith S., Eremin J.M., El-Sheemy M., Eremin O. Neoadjuvant chemotherapy in women with large and locally advanced breast cancer: chemoresistance and prediction of response to drug therapy // Surgeon. 2006. Vol. 4 (4). P. 211–219.
13. de Jongh C.M., Khrenova L., Kezic S. Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis // Contact Dermatitis. 2008. Vol. 58 (5). P. 263–268.
14. DeNardo D.G., Brennan D.J., Rexhepaj E. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy // Cancer Discov. 2011. Vol. 1 (1). P. 54–67.
15. Farmer P., Bonnefoi H., Anderle P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer // Nat. Med. 2009. Vol. 15 (1). P. 68–74.
16. Finak G., Bertos N., Pepin F. et al. Stromal gene expression predicts clinical outcome in breast cancer // Nat. Med. 2008. Vol. 14 (5). P. 518–527.
17. Fridman W.H., Teillaud J.L., Sautes-Fridman C. et al. The ultimate goal of curative anti-cancer therapies: inducing an adaptive anti-tumor immune response // Front. Immunol. 2011. Vol. 2 (66).
18. Goldhirsch А., Glick J.H., Gelber R. D. et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005 // Ann Oncol. 2005. Vol. 16 (10). P. 1569–1583.
19. Gonzalez-Angulo A.M., Morales-Vasquez F., Hortobagyi G.N. Overview of resistance to systemic therapy in patients with breast cancer // Adv. Exp. Med. Biol. 2007. Vol. 608. P. 1–22.
20. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation // Cell. 2011. Vol. 144 (5). P. 646–674.
21. Hannani D., Sistigu A., Kepp O. et al. Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy // Cancer J. 2011. Vol. 17 (5). P. 351–358.
22. Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M. et al. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response // Cancer Chemother. Pharmacol. 2013. Vol. 71. P. 153–163.
23. Lutsiak M.E., Semnani R.T., De Pascalis R. et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide // Blood. 2005. Vol. 105 (7). P. 2862–2868.
24. Mahdaviani S.A., Rezaei N., Moradi B. et al. Proinflammatory cytokine gene polymorphisms among Iranian patients with asthma // J. Clin. Immunol. 2009. Vol. 29 (1). P. 57–62.
25. Miyazoe S., Hamasaki K., Nakata K. et al. Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus // Am. J. Gastroenterol. 2002. Vol. 97 (8). P. 2086–2092.
26. Mumm J.B., Emmerich J., Zhang X. et al. IL-10 elicits IFNγ- dependent tumor immune surveillance // Cancer Cell. 2011. Vol. 20 (6). P. 781–796.
27. Obeid M., Tesniere A., Ghiringhelli F. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death // Nat. Med. 2007. Vol. 13 (1). P. 54–61.
28. Place A.E., Huh S.J., Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment // Breast Cancer Res. 2011. Vol. 13 (6). P. 227.
29. Polyak K., Vogt P.K. Progress in breast cancer research // Proc Natl. Acad. Sci. USA. 2012. Vol. 109. P. 2715–2717.
30. Shin H.D., Park B.L., Kim L.H. et al. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma // Hum. Mol. Genet. 2003. Vol. 12 (8). P. 901–906.
31. Silvestre J.S., Mallat Z., Duriez M. et al. Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb. // Circ. Res. 2000. Vol. 87 (6). P. 448–452.
32. Suzuki E., Kapoor V., Jassar A.S. et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumorbearing animals and enhances antitumor immune activity // Clin. Cancer. Res. 2005. Vol. 11 (18). P 6713–6721.
33. Wind N.S., Holen I. Multidrug Resistance in Breast Cancer: From In Vitro Models to Clinical Studies // Int. J. Breast Cancer. 2011. Vol. 2011. P. 1–12.
34. Zhang X., Kiechle F. Hoechst 33342-Induced Apoptosis is Associated with Decreased Immunoreactive Topoisomerase I and Topoisomerase I-DNA Complex Formation // Ann. Clin. Labor. Scien. 2001. Vol. 31 (2). P. 187–198.
35. Zitvogel L., Apetoh L., Ghiringhelli F., Kroemer G. Immunological aspects of cancer chemotherapy // Nat. Rev. Immunol. 2008. Vol. 8 (1). P. 59–73.
Review
For citations:
Kukharev Y.V., Stakheeva M.N., Doroshenko A.V., Litvyakov N.V., Babyshkina N.N., Slonimskaya E.M., Cherdyntseva N.V. RELATIONSHIP OF THE IMMUNOLOGICAL PARAMETRES WITH NEOADJUVANT CHEMOTHERAPY EFFECTIVENESS IN BREAST CANCER PATIENTS. Siberian journal of oncology. 2013;(2):50-57. (In Russ.)
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