CANCER TREATMENT BY REGULATING MACROPHAGE PROLIFERATION

Mamatova Irodakhon Yusupovna, Fozilova Gavkharoy Erkinjonovna

Authors

Mamatova Irodakhon Yusupovna, Fozilova Gavkharoy Erkinjonovna Department of Biological Chemistry Andijan State Medical Institute

Keywords:

Macrophage Proliferation, Tumor-Associated Macrophages (TAMs), Cancer Therapy, Targeted Therapy, Tumor Microenvironment (TME), CSF-1R, Immunotherapy, Cytokines.

Abstract

Tumor-associated macrophages (TAMs) are a major component of the leukocyte infiltrate in most solid tumors and play a critical, often pro-tumorigenic, role in cancer progression. They contribute to tumor growth, angiogenesis, immunosuppression, metastasis, and resistance to therapy. The accumulation of TAMs within the tumor microenvironment (TME) results from both the recruitment of monocytic precursors from the circulation and the local proliferation of resident macrophages. Recent evidence highlights that in situ proliferation significantly contributes to the TAM population in various cancers. This self-renewal capacity makes macrophage proliferation an attractive therapeutic target. This review discusses the significance of macrophage proliferation in the TME, the key molecular drivers, and the emerging therapeutic strategies aimed at inhibiting this process. We explore preclinical and clinical evidence for agents targeting pathways crucial for macrophage proliferation, such as the colony-stimulating factor 1 (CSF-1)/CSF-1 receptor (CSF-1R) axis, and discuss their impact on tumor growth and the immune landscape. Furthermore, we consider the potential of combining macrophage proliferation inhibitors with other anti-cancer treatments, including chemotherapy, radiotherapy, and immunotherapy, to enhance therapeutic efficacy. Challenges such as ensuring specificity for pro-tumor TAMs and overcoming compensatory mechanisms are also addressed, along with future perspectives for this promising therapeutic approach

References

Noy, R., & Pollard, J. W. (2014). Tumor-associated macrophages: from mechanisms to therapy. Immunity, 41(1), 49–61.

Mantovani, A., Sozzani, S., Locati, M., Allavena, P., & Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology, 23(11), 549–555.

Franklin, R. A., Liao, W., Sarkar, A., Kim, M. V., Bivona, M. R., Liu, K., ... & Li, M. O. (2014). The cytokine GM-CSF promotes sarcoma proliferation and TSLP-mediated Th2 differentiation. Nature Immunology, 15(10), 925–935. (Demonstrates local proliferation)

Van Overmeire, E., Laoui, D., Keirsse, J., Van Ginderachter, J. A., & De Baetselier, P. (2014). Mechanisms driving macrophage functional diversity and polarization in cancer. Cellular and Molecular Life Sciences, 71(24), 4841–4860.

Quatromoni, J. G., & Eruslanov, E. (2012). Tumor-associated macrophages: function, phenotype, and link to prognosis in human cancer. American Journal of Translational Research, 4(4), 376–389.

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

Gordon, S. (2003). Alternative activation of macrophages. Nature Reviews Immunology, 3(1), 23–35.

Mills, C. D. (2012). M1 and M2 Macrophages: Oracles of Health and Disease. Critical Reviews in Immunology, 32(6), 463–488.

Pollard, J. W. (2004). Tumour-educated macrophages promote tumour progression and metastasis. Nature Reviews Cancer, 4(1), 71–78.

Zhang, Q. W., Liu, L., Gong, C. Y., Shi, H. S., Zeng, Y. H., Wang, X. Z., ... & Liu, Z. Q. (2012). Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One, 7(12), e50946.

Qian, B. Z., & Pollard, J. W. (2010). Macrophage diversity enhances tumor progression and metastasis. Cell, 141(1), 39–51.

Bottazzi, B., Polentarutti, N., Acero, R., Balsari, A., Boraschi, D., Ghezzi, P., ... & Mantovani, A. (1983). Regulation of the macrophage content of neoplasms by chemoattractants. Science, 220(4593), 210–212. (Early work, context for proliferation studies)

Stanley, E. R., & Chitu, V. (2014). CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor Perspectives in Biology, 6(6), a021857.

Murray, P. J. (2017). Macrophage Polarization. Annual Review of Physiology, 79, 541–566.

Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., ... & Merad, M. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330(6005), 841–845. (Microglia proliferation)

DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., ... & Coussens, L. M. (2011). Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discovery, 1(1), 54–67.

Hume, D. A., & MacDonald, K. P. (2012). Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood, 119(8), 1810–1820.

Nandi, S., Cioce, M., Yeung, Y. G., Nieves, E., Tesfa, L., Lin, H., ... & Stanley, E. R. (2013). Receptor-type protein-tyrosine phosphatase ζ is a functional receptor for interleukin-34. Journal of Biological Chemistry, 288(31), 22003–22017. (IL-34 role)

Fleetwood, A. J., Lawrence, T., Hamilton, J. A., & Cook, A. D. (2007). Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. Journal of Immunology, 178(8), 5245–5252.

Gieseck, R. L., Wilson, M. S., & Wynn, T. A. (2018). Type 2 immunity in tissue repair and fibrosis. Nature Reviews Immunology, 18(1), 62–76.

Pello, O. M., De Pizzol, M., Mirolo, M., Soucek, L., Zambrano, A. M., Mussi, V., ... & Fantin, A. (2012). Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood, 119(2), 411–421.

Pyonteck, S. M., Akkari, L., Schuhmacher, A. J., Bowman, R. L., Sevenich, L., Quail, D. F., ... & De Stanchina, E. (2013). CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nature Medicine, 19(10), 1264–1272.

Strachan, D. C., Ruffell, B., O’Loughlin, E., G لائسنس یافتہ, Coussens, L. M. (2013). CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the recruitment of tumor-promoting macrophages. Cancer Research, 73(24), 7376–7389.

Tap, W. D., Wainberg, Z. A., Anthony, S. P., Ibrahim, P. N., Cappelleri, J. C., Curtis, C. M., ... & Gelderblom, H. (2015). Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. New England Journal of Medicine, 373(5), 428–437.

Ries, C. H., Cannarile, M. A., Hoves, S., Benz, J., Wartha, K., Runza, V., ... & Weisser, M. (2014). Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell, 25(6), 846–859.

Goel, S., DeCristo, M. J., Watt, A. C., BrinJones, H., Sceneay, J., Li, B. B., ... & McArthur, G. A. (2017). CDK4/6 inhibition triggers anti-tumour immunity. Nature, 548(7668), 471–475.

Zhu, Y., Knolhoff, B. L., Meyer, M. A., Nywening, T. M., West, B. L., Luo, J., ... & DeNardo, D. G. (2014). CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Research, 74(18), 5057–5069.

Ahn, G. O., Tseng, D., Liao, C. H., Dorie, M. J., Czechowicz, A., & Brown, J. M. (2010). Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proceedings of the National Academy of Sciences, 107(18), 8363–8368. (Related to myeloid cells and radiation)

Rivera, L. B., & Bergers, G. (2015). Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends in Immunology, 36(4), 240–249.