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Invited researcher Chudakov Dmitriy Mikhaylovich
Contract number
14.W03.31.0005
Time span of the project
2017-2021

As of 15.02.2021

13
Number of staff members
10
scientific publications
1
Objects of intellectual property
General information

Name of the project: Clonal composition of tumor-infiltrating T lymphocytes as a forecasting and predictive marker in treatment of oncological illnesses

Strategy for Scientific and Technological Development Priority Level: в

Goals and objectives
Research directions:

  • Impact of immunotherapy using checkpoint inhibitors on clonal composition of functional subpopulations of T lymphocytes (observed in model mice and clinical samples);
  • Fate of tumor-specific T lymphocytes in development of illness and during response to immunotherapy (in model mice);
  • Aging of adaptive immunity, cancer, immunotherapy (in model mice);
  • Clonality of CD4+, CD4+Treg, CD8+, and CD8+PD1+ Т lymphocytes in tumors and peripheral blood as a factor for forecasting in color cancer patients (in clinical samples).

The practical value of the study
  1. A study of the clonal structure of the repertoire of tumor-infiltrating T- and B-lymphocytes in human cutaneous melanoma was carried out. It was shown for the first time that the pronounced presence of clonal, hypermutating populations of B-lymphocytes and IgG1-producing plasma cells in a tumor - in the composition of tertiary lymphoid structures or in metastatic lymph nodes - is associated with a significantly more favorable prognosis. The same pattern is observed for non-papillary bladder cancer and lung adenocarcinoma. Active work is underway in this direction.
  2. For the first time, an approach to the analysis of the repertoires of tumor-infiltrating T lymphocytes by free DNA of blood plasma has been developed.
  3. A new approach to the analysis of sorted subpopulations of tumor-infiltrating lymphocytes has been developed, which combines obtaining informative repertoires of immune receptors and transcriptome profiles.
  4. In a mouse model of melanoma, the clustering of clonal populations of T-lymphocytes in the tumor is shown. It was shown that the response to therapy with antibodies to PD1 depends on the appearance of clonal expansions of CD4 and CD8 T lymphocytes, and the long-term preservation of the increased clonality of the repertoire over time. Shown is the preferential activation of CD4 T-lymphocytes in response to therapy with blocking antibodies to CTLA-4, activation of CD4 and CD8 T-lymphocytes in response to therapy with blocking antibodies to PD1, activation of CD8, CD4, Treg and B-lymphocytes during therapy with agonist antibodies to OX40.

Education and career development:

  1. 5 PhD theses have been defended.
  2. On the basis of the laboratory, 2 Ph.D. theses of graduate students are being prepared.
  3. Developed and implemented a special course "Immunology" for postgraduate students of PIMU in the areas of training: 30.06.01 Fundamental medicine, 06.06.01 Biological sciences.
  4. Employees of the laboratory conduct lectures for students at the School of Young Scientists at the Research Institute of Experimental Oncology and Biomedical Technologies of PIMU.

Other results:

Members of the academic staff of the Laboratory participate with invited talks in such conferences as «SPIE Photonics West», «Topical problems of biophotonics», «FLIM workshops», «17th Congress of the European Society for Photobiology», «Systems Biology of Adaptive Immunity», «Antibody Engineering & Therapeutics Europe», «Immuno-Oncology, Laser Applications in Life Sciences Conference» (LALS 2018), «5th «European Congress of Immunology» (ECI 2018), «2nd International Meeting on: stochasticity and control in adaptive immune repertoires, Lymphocyte antigen receptor signalling», «Science of the Future – Science of the Youth», 5th Meeting of Pharmacologists of Russia «Scientific basis of search and creation of new medications», «Prospective directions of physical and chemical biology d biotechnology», «5th All-Russian Conference in Molecular Oncology», 10th Meeting of Oncologists of Russia. Over the period between 2017 and 2019 members of the academic staff of the Laboratory have delivered 9 invited talks.

Collaborations:

  • Institute of Bioorganic Chemistry of the Russian Academy of Sciences (Russia): joint research, collaborative publications, scientific seminars for experience exchange, mutual consulting.
  • Memorial Sloan Kettering Cancer Center (USA), Masaryk University (Czech Republic): joint scientific events, collaborative publications, exchange of experience, collaboration in analysis of obtained results.
  • N.I. Pirogov Russian National Medical University (Russia), Netherlands Cancer Institute (the Netherlands), Institute of Immunology Federal Biomedical Agency of Russia (Russia): joint research, collaborative publications, scientific seminars for experience exchange, mutual consulting.

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Sharonov G.V., Serebrovskaya E.O., Yuzhakova D.V., Britanova O.V., Chudakov D.M.
B Cells, plasma cells and antibody repertoires in the tumour microenvironment. Nature Reviews Immunology. 2020 May; 20(5)
Zhigalova E.A., Izosimova A.I., Yuzhakova D.V., Volchkova L.N., Shagina I.A., Turchaninova M.A., Serebrovskaya E.O., Zagaynova E.V., Chudakov D.M., Sharonov G.V.
RNA-Seq-Based TCR profiling reveals persistently increased intratumoral clonality in responders to Anti-PD-1 therapy. Frontiers in Oncology. 2020 Apr; 10: 385
Fan X., Moltedo B., Mendoza A., Davydov A.N., Faire M.B., Mazutis L., Sharma R., Pe'er D., Chudakov D.M., Rudensky A.Y.
CD49b defines functionally mature Treg cells that survey skin and vascular tissues. Journal of experimental medicine. 2018 Nov 5; 215(11)
Bolotin D.A., Poslavsky S., Davydov A.N., Chudakov D.M.
Reply to "Evaluation of immune repertoire inference methods from RNA-seq data". Nature biotechnology. 2018 Nov 9; 36(11)
Druzhkova I., Ignatova N., Prodanets N., Kiselev N., Zhukov I., Shirmanova M., Zagainov V., Zagaynova E.
E-Cadherin in Colorectal Cancer: Relation to Chemosensitivity. Clinical colorectal cancer. 2019 Mar; 18(1)
Pogorelyy M.V., Minervina A.A., Shugay M., Chudakov D.M., Lebedev Y.B., Mora T., Walczak A.M.
Detecting T cell receptors involved in immune responses from single repertoire snapshots.PLOS Biology. 2019 Jun 13; 17(6)
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