Immunologic aspects of colorectal cancer progression

Colorectal cancer remains in the leading positions in the structures of morbidity and mortality among both sexes. A large number of studies are aimed to reveal new biomarkers targeted at both early diagnosis and improving the effectiveness of drug therapy. Colorectal carcinoma (CC) is heterogeneous in its morphological, molecular and immunological aspects and is a heterogeneous disease. The existing molecular genetic classifications and biomarkers capable of predicting the effectiveness of therapy aren’t optimal enough. New prognostic markers would make it possible to identify a subgroup of patients with a high risk of tumor recurrence, for whom enhanced monitoring and diagnostic monitoring should be established, as well as the selection of highly effective methods in the treatment of colorectal cancer. It has been established that some immune cells in the tumor microenvironment are able to stimulate the development of disease progression. Cytokines and chemokines in the tumor microenvironment stimulate the development of metastases, and their serum levels reflect the current inflammatory response in the tumor tissue. The identification and analysis of immune markers involved in the processes of metastasis and the mechanisms of progression remains an important task of modern medicine. The purpose of the study was to analyze modern ideas about the importance of the immunological microenvironment in the progression of colorectal cancer. The effect of molecular heterogeneity of the tumor on the development of metastases, as well as on resistance to ongoing antitumor therapy. The review reflects the immunological characteristics of CC, including in the context of molecular biological subtypes. It describes the involvement of cells of the immune system (lymphocytes, macrophages) and their products (cytokines, chemokines) in the progression of colorectal cancer, including in the processes of neoangiogenesis, as well as the relationship of the T- and B-cell composition of the tumor microenvironment on the course of the disease. The review also shows the immunogenomic stratification of CC, which can be used to predict the response to immunotherapy for colorectal cancer.

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7–33. https://doi.org/10.3322/caac.21654

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209–249. https://doi.org/10.3322/caac.21660

3. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89–103. https://doi.org/10.5114/pg.2018.81072

4. Osombaev MSh, Dzhekshenov MD, Satybaldiev OA, Abdrasulov KD, Makimbetov EK, Kuzikeev MA. Epidemiology of colorectal cancer. Scientific review. Medical Sciences. 2021;1(7):37–42. (In Russ.). https://doi.org/10.17513/srms.1169, EDN: LYEMDE

5. Vodolazhsky DI, Antonets AV, Dvadnenko KV, Vladimirova LYu, Gevorkyan YuA, Kasatkin VF, et al. The relationship of KRAS gene mutations with the clinical and pathological features of colorectal cancer in patients in the South of Russia. International Journal of Experimental Education. 2014;1(1):65–68. (In Russ.).

6. The state of cancer care for the Russian population in 2021. Edited by A. D. Kaprin, V. V. Starinsky, A. O. Shakhzadova. Moscow: P. A. Herzen MNIOI – Branch of the National Medical Research Radiological Center, 2022, 239 p. (In Russ.)

7. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020 Mar 20;5(1):22. https://doi.org/10.1038/s41392-020-0116-z

8. Giordano G, Remo A, Porras A, Pancione M. Immune Resistance and EGFR Antagonists in Colorectal Cancer. Cancers (Basel). 2019 Jul 31;11(8):1089. https://doi.org/10.3390/cancers11081089

9. Woolston A, Khan K, Spain G, Barber LJ, Griffiths B, Gonzalez-Exposito R, et al. Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. Cancer Cell. 2019 Jul 8;36(1):35-50.e9. https://doi.org/10.1016/j.ccell.2019.05.013

10. Malki A, ElRuz RA, Gupta I, Allouch A, Vranic S, Al Moustafa AE. Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements. Int J Mol Sci. 2020 Dec 24;22(1):130. https://doi.org/10.3390/ijms22010130

11. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012 Jul 18;487(7407):330–337. https://doi.org/10.1038/nature11252

12. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015 Nov;21(11):1350–1356. https://doi.org/10.1038/nm.3967

13. Wang Y, Han G, Wang K, Liu G, Wang R, Xiao H, et al. Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF. Cancer Res. 2014 Feb 1;74(3):716–726. https://doi.org/10.1158/0008-5472.CAN-13-1459

14. Gaiani F, Marchesi F, Negri F, Greco L, Malesci A, de’Angelis GL, et al. Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes. Int J Mol Sci. 2021 May 15;22(10):5246. https://doi.org/10.3390/ijms22105246

15. Hunter KW, Amin R, Deasy S, Ha NH, Wakefield L. Genetic insights into the morass of metastatic heterogeneity. Nat Rev Cancer. 2018 Apr;18(4):211–223. https://doi.org/10.1038/nrc.2017.126

16. Reutova EV, Laktionov KK, Ardzinba MS, Nelyubina LA, Arzumanyan AL. Acquired resistance to EGFR tyrosine kinase inhibitors: ways to overcome. Medical Council. 2017;(14):24–28. (In Russ.). https://doi.org/10.21518/2079-701X-2017-14-24-28

17. Becht E, de Reyniès A, Giraldo NA, Pilati C, Buttard B, Lacroix L, et al. Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy. Clin Cancer Res. 2016 Aug 15;22(16):4057–4066. https://doi.org/10.1158/1078-0432.CCR-15-2879

18. Karpinski P, Rossowska J, Sasiadek MM. Immunological landscape of consensus clusters in colorectal cancer. Oncotarget. 2017 Dec 1;8(62):105299–105311. https://doi.org/10.18632/oncotarget.22169

19. Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer. 2019 Dec 1;125(23):4139–4147. https://doi.org/10.1002/cncr.32163

20. Okita A, Takahashi S, Ouchi K, Inoue M, Watanabe M, Endo M, et al. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget. 2018 Apr 10;9(27):18698–18711. https://doi.org/10.18632/oncotarget.24617

21. Zafari N, Khosravi F, Rezaee Z, Esfandyari S, Bahiraei M, Bahramy A, et al. The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches. J Clin Lab Anal. 2022 Aug;36(8):e24585. https://doi.org/10.1002/jcla.24585

22. Nikipelova EA, Kit OI, Shaposhnikov AV, Zlatnik EYu, Novikova IA, Vladimirova LYu, et al. Immunological criteria for the development of distant metastases of colon cancer. News of higher educational institutions. The North Caucasus region. Series: Natural Sciences. 2017;(3-2(195-2)):96–101. (In Russ.). https://doi.org/10.23683/0321-3005-2017-3-2-96-101, EDN: ZQTDAB

23. Kit OI, Dzhenkova EA, Mirzoyan EA, Sagakyants AB, Bondarenko ES, Zlatnik EYu, et al. Features of local cellular immunity in colon cancer, depending on the localization of the tumor process. Modern Problems of Science and Education. 2022;3:86. (In Russ.). https://doi.org/10.17513/spno.31695

24. Mager LF, Wasmer MH, Rau TT, Krebs P. Cytokine-Induced Modulation of Colorectal Cancer. Front Oncol. 2016 Apr 19;6:96. https://doi.org/10.3389/fonc.2016.00096

25. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015 Apr 13;27(4):462–472. https://doi.org/10.1016/j.ccell.2015.02.015

26. Coffelt SB, de Visser KE. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol. 2015 Apr;36(4):198–216. https://doi.org/10.1016/j.it.2015.02.006

27. Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016 Jul;16(7):447–462. https://doi.org/10.1038/nrc.2016.54

28. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014 Jul 17;41(1):49–61. https://doi.org/10.1016/j.immuni.2014.06.010

29. Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol. 2012 Aug;22(4):327–334. https://doi.org/10.1016/j.semcancer.2012.03.004

30. Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019 Jun;19(6):307–325. https://doi.org/10.1038/s41568-019-0144-6

31. Liu Q, Yang C, Wang S, Shi D, Wei C, Song J, et al. Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal. 2020 Mar 30;18(1):51. https://doi.org/10.1186/s12964-020-00557-2

32. Laghi L, Negri F, Gaiani F, Cavalleri T, Grizzi F, De’ Angelis GL, et al. Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer. Int J Mol Sci. 2020 Dec 18;21(24):9680. https://doi.org/10.3390/ijms21249680

33. Lal N, Beggs AD, Willcox BE, Middleton GW. An immunogenomic stratification of colorectal cancer: Implications for development of targeted immunotherapy. Oncoimmunology. 2015 Mar;4(3):e976052. https://doi.org/10.4161/2162402X.2014.976052

34. Zheng X X, Ma Y, Bai Y, Huang T, Lv X, Deng J, et al. Identification and validation of immunotherapy for four novel clusters of colorectal cancer based on the tumor microenvironment. Front Immunol. 2022;13:984480. https://doi.org/10.3389/fimmu.2022.984480