Interrelation of HLA-I and class II major histocompatibility complex molecules with clinical and morphological signs of breast cancer: A retrospective cohort study

Cover Page

Cite item

Full Text

Abstract

Background. For a long time, interest in the HLA peptide complex is unabated, the clinical significance of which in cancer is still the subject of intense debate. Through the presentation of HLA antigens, tumor cells become available for recognition and destruction by effector cells of the immune system. A detailed analysis of the expression status of HLA molecules by breast cancer cells is of both scientific and important practical value. It can provide additional information about the immune system to determine a further strategy for treating breast cancer.

Aim. To evaluate the frequency of expression of HLA-I and class II molecules by breast cancer cells and to determine its relationship with the morphological and clinical characteristics of the tumor.

Materials and methods. This study included 82 patients with breast cancer who received treatment at the Blokhin National Medical Research Center of Oncology. Immunophenotyping of the primary tumor was performed by the immunohistochemical method (immunofluorescent staining) on cryostat sections. The reaction was evaluated using a ZEISS luminescent microscope (AXIOSKOP, Germany). The frequency of expression of HLA-I and class II molecules was studied depending on the clinical and morphological characteristics of breast cancer.

Results. It was found that the frequency of expression of HLA I and II class molecules by breast cancer cells differed. HLA class I antigens are preserved in almost half of the cases 54.5%, while HLA class II antigens are preserved in 22.0%. Associations of molecules of the major histocompatibility complex with clinical and morphological signs of breast cancer were revealed. The frequency of HLA-DR negative cases increases in the stage advanсed (p=0.029). The frequency of monomorphic expression of HLA class II with T1 tumor was 50% versus 0% at T4 tumor (p=0.032). Estrogen receptor-negative tumors in most cases did not express HLA-II class (85.2% vs 64%; p=0.034). No connection with other clinical and morphological features of the tumor has been established.

Conclusion. In most cases of breast cancer, the expression of HLA class II molecules is lost, while the expression of HLA class I is preserved in half of the cases. Monomorphic expression of HLA class II is characteristic of the early stage of breast cancer development and predominantly of receptor-positive tumors.

About the authors

Svetlana V. Chulkova

Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University

Email: kapelovich@hpmp.ru
ORCID iD: 0000-0003-4412-5019

Cand. Sci. (Med.), Blokhin National Medical Research Center of Oncology, Assoc. Prof.

Russian Federation, Moscow; Moscow

Elena N. Sholokhova

Blokhin National Medical Research Center of Oncology

Email: enshell@mail.ru
ORCID iD: 0000-0002-1456-1904

Cand. Sci. (Med.), Blokhin National Medical Research Center of Oncology

Russian Federation, Moscow

Irina V. Poddubnaya

Russian Medical Academy of Continuous Professional Education

Email: chulkova@mail.ru
ORCID iD: 0000-0002-0995-1801
SPIN-code: 1146-9889

D. Sci. (Med.), Prof., Acad. RASn Medical Academy of Continuous Professional Education

Russian Federation, Moscow

Ivan S. Stilidi

Blokhin National Medical Research Center of Oncology; Pirogov Russian National Research Medical University

Email: chulkova@mail.ru
ORCID iD: 0000-0002-0493-1166

D. Sci. (Med.), Prof., Acad. RAS

Russian Federation, Moscow; Moscow

Dmitrii A. Burov

Yevdokimov Moscow State University of Medicine and Dentistry

Email: chulkova@mail.ru

Senior Laboratory Assistant

Russian Federation, Moscow

Nikolai N. Tupitsyn

Blokhin National Medical Research Center of Oncology

Author for correspondence.
Email: chulkova@mail.ru
ORCID iD: 0000-0003-3966-128X

D. Sci. (Med.), Prof.

Russian Federation, Moscow

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209-49.
  2. McCormack V, McKenzie F, Foerster M, et al. Breast cancer survival and survival gap apportionment in sub-Saharan Africa (ABC-DO): a prospective cohort study. The Lancet Global Health. 2020;8(9):e1203-12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/32827482. Accessed: 01.12.2021.
  3. Титов К.С., Казаков А.М., Барышникова М.А., и др. Некоторые молекулярные и иммунологические факторы прогноза трижды негативного рака молочной железы. Онкогинекология. 2019;4(32):26-34 [Titov KS, Kazakov AM, Baryshnikova MA, et al. Nekotorye molekulyarnye i immunologicheskie faktory prognoza trizhdy negativnogo raka molochnoi zhelezy. Onkoginekologiya. 2019;4(32):26-34 (in Russian)].
  4. Mutebi M, Anderson BO, Duggan C, et al. Breast cancer treatment: A phased approach to implementation. Cancer. 2020;126(Suppl.10):236578. Available at: http://www.ncbi.nlm.nih.gov/pubmed/32348571. Accessed: 01.12.2021.
  5. Рябчиков Д.А., Абдуллаева Э.И., Дудина И.А., и др. Роль микро-РНК в канцерогенезе и прогнозе злокачественных новообразований молочной железы. Вестник Российского научного центра рентгенорадиологии. 2018;18(2):5 [Ryabchikov DA, Abdullaeva EI, Dudina IA, et al. Rol' mikro-RNK v kantserogeneze i prognoze zlokachestvennykh novoobrazovanii molochnoi zhelezy. Vestnik Rossiiskogo nauchnogo tsentra rentgenoradiologii. 2018;18(2):5 (in Russian)].
  6. Sabbatino F, Liguori L, Polcaro G, et al. Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients. Int J Mol Sci. 2020;21:7295. doi: 10.3390/ijms21197295
  7. Shukla A, Cloutier M, Santharam AM, et al. The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy. Int J Mol Sci. 2021;22(4):1964. doi: 10.3390/ijms22041964
  8. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genom Hum Genet. 2013;14:301-23.
  9. Trowsdale J. Genomic structure and function in the MHC. Trends Genet. 1993;9:117-22.
  10. Norman PJ, Norberg SJ, Guethlein LA, et al. Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Genome Res. 2017;27:813-23.
  11. Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889-99.
  12. Neefjes J, Jongsma MLM, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11:823-36.
  13. Rock KL, Reits E, Neefjes J. Present Yourself! By MHCClass I and MHCClass II Molecules. Trends Immunol. 2016;37:724-37.
  14. Holling TM, Schooten E, Van Den Elsen PJ. Function and regulation of MHC class II molecules in T-lymphocytes: Of mice and men. Hum Immunol. 2004;65:282-90.
  15. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol. 2013;31:443-73.
  16. Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 2019;234:8509-21.
  17. Cruz FM, Colbert JD, Merino E, et al. The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules. Annu Rev Immunol. 2017;35:149-76.
  18. Leone P, Shin EC, Perosa F, et al. MHC class I antigen processing and presenting machinery: Organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105:1172-87.
  19. Thielens A, Vivier E, Romagné F. NK cell MHC class I specific receptors (KIR): From biology to clinical intervention. Curr Opin Immunol. 2012;24:239-45.
  20. Cabrera T, Maleno I, Collado A, et al. Analysis of HLA class I alterations in tumors: Choosing a strategy based on known patterns of underlying molecular mechanisms. Tissue Antigens. 2007;69 (Suppl. S1):264-8.
  21. Cai L, Michelakos T, Yamada T, et al. Defective HLAclass I antigen processing machinery in cancer. Cancer Immunol Immunother. 2018;67:999-1009.
  22. Garrido F, Algarra I. MHC antigens and tumor escape from immune surveillance. Adv Cancer Res. 2001;83:117-58.
  23. Martin HP, Brian LH, Hans ChB, et al. Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors. OncoImmunology. 2017;6(5):e1305531. doi: 10.1080/2162402X.2017.1305531
  24. Sinn BV, Weber KE, Schmitt WD, et al. Human leucocyte antigen class I in hormone receptor-positive, HER2-negative breast cancer: association with response and survival after neoadjuvant chemotherapy. Breast Cancer Res. 2019;21:142. doi: 10.1186/s13058-019-1231-z
  25. Артамонова Е.В. Роль иммунофенотипирования в диагностике и прогнозе рака молочной железы. Иммунология гемопоэза. 2009;1(9):8-52 [Artamonova EV. Rol' immunofenotipirovaniia v diagnostike i prognoze raka molochnoi zhelezy. Immunologiia gemopoeza. 2009;1(9):8-52 (in Russian)].
  26. Буров Д.А., Безнос О.А., Воротников И.К., и др. Клиническое значение экспрессии молекул гистосовместимости на клетках рака молочной железы. Иммунология гемопоэза. 2016;2(14):33-53 [Burov DA, Beznos OA, Vorotnikov IK, et al. Klinicheskoie znacheniie ekspressii molekul gistosovmestimosti na kletkakh raka molochnoi zhelezy. Immunologiia gemopoeza. 2016;2(14):33-53 (in Russian)].
  27. Беришвили А.И., Тупицын Н.Н., Лактионов К.П. Иммунофенотипическая характеристика отечно-инфильтративной формы рака молочной железы. Опухоли женской репродуктивной системы. 2009;3-4:15-9 [Berishvili AI, Tupitsyn NN, Laktionov KP. Immunophenotypic characteristics of inflammatory breast cancer. Tumors of Female Reproductive System. 2009;3-4:15-9 (in Russian)].
  28. Енгай Д.А. Иммунологическая характеристика Pgp170 позитивного рака молочной железы: дис. … кандидат мед. наук. М., 2008 [Engay DA. Immunologicheskaia kharakteristika Pgp170 pozitivnogo raka molochnoi zhelezy: dis. … kand. med. nauk. Moscow, 2008 (in Russian)].
  29. Rodriguez JA. HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T-cell activation. Oncol Lett. 2017;14:4415-27.
  30. Haen SP, Loffler MW, Rammensee HG, Brossart P. Towards new horizons: Characterization, classification and implications of the tumour antigenic repertoire. Nat Rev Clin Oncol. 2020;17:595-610.
  31. Yan M, Jene N, Byrne D, et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Res. 2011;13:R47.
  32. Olkhanud PB, Damdinsuren B, Bodogai M, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Res. 2011;71:3505-15.
  33. Munir MT, Kay MK, Kang MH, et al. Tumor-Associated Macrophages asMultifaceted Regulators of Breast Tumor Growth. Int J Mol Sci. 2021;22:6526.
  34. Lim B, Woodward WA, Wang X, et al. Inflammatory breast cancer biology: The tumour microenvironment is key. Nat Rev Cancer. 2018;18:485-99.
  35. Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: Detection, characterization and clinical implication. Breast Cancer. 2017;24:3-15.

Supplementary files

Supplementary Files
Action
1. JATS XML
2. Fig.1.

Download (48KB)
3. Fig.2.

Download (73KB)
4. Fig.3.

Download (63KB)

Copyright (c) 2023 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies