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CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model

Abstract

The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.

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Fig. 1: Increased number of TAMs is associated with tumor progression in a sporadic SHH-MB mouse model.
Fig. 2: The amount of immune cell infiltration in human SHH-MB samples does not correlate with driver mutation.
Fig. 3: Depletion of Tregs or T cells in Atoh1-SmoM2 mice does not alter mouse survival.
Fig. 4: Depletion of TAMs prolongs mouse survival and blocks tumor progression in most Atoh1-SmoM2 mice.
Fig. 5: Atoh1-SmoM2 tumors treated for 4 weeks with PLX show a decrease of monocytes/macrophages and an increase of CD8 cytotoxic T cells.
Fig. 6: Depletion of TAMs in Atoh1-SmoM2 mice leads to an increase of pro-inflammatory T cells.
Fig. 7: Depletion of TAMs in Atoh1-SmoM2 mice leads to a pro-inflammatory tumor microenvironment.

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References

  1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.

    PubMed  Google Scholar 

  2. McNeill KA. Epidemiology of brain tumors. Neurol Clin. 2016;34:981–98.

    PubMed  Google Scholar 

  3. Ramaswamy V, Taylor MD. Medulloblastoma: from myth to molecular. J Clin Oncol. 2017;35:2355–63.

    CAS  PubMed  Google Scholar 

  4. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathologica. 2012;123:465–72.

    CAS  PubMed  Google Scholar 

  5. Archer TC, Ehrenberger T, Mundt F, Gold MP, Krug K, Mah CK, et al. Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell. 2018;34:396–410. e398.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31:737–54. e736.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al. The whole-genome landscape of medulloblastoma subtypes. Nature. 2017;547:311–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bockmayr M, Mohme M, Klauschen F, Winkler B, Budczies J, Rutkowski S, et al. Subgroup-specific immune and stromal microenvironment in medulloblastoma. Oncoimmunology. 2018;7:e1462430.

    PubMed  PubMed Central  Google Scholar 

  9. Margol AS, Robison NJ, Gnanachandran J, Hung LT, Kennedy RJ, Vali M, et al. Tumor-associated macrophages in SHH subgroup of medulloblastomas. Clin Cancer Res. 2015;21:1457–65.

    CAS  PubMed  Google Scholar 

  10. Maximov V, Chen Z, Wei Y, Robinson MH, Herting CJ, Shanmugam NS, et al. Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma. Nat Commun. 2019;10:2410.

    PubMed  PubMed Central  Google Scholar 

  11. Pham CD, Flores C, Yang C, Pinheiro EM, Yearley JH, Sayour EJ, et al. Differential immune microenvironments and response to immune checkpoint blockade among molecular subtypes of murine medulloblastoma. Clin Cancer Res. 2016;22:582–95.

    CAS  PubMed  Google Scholar 

  12. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer metastasis Rev. 2006;25:315–22.

    PubMed  Google Scholar 

  13. Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31:326–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang M, McKay D, Pollard JW, Lewis CE. Diverse functions of macrophages in different tumor microenvironments. Cancer Res. 2018;78:5492–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2016;352:aad3018.

    PubMed  PubMed Central  Google Scholar 

  17. Yao M, Ventura PB, Jiang Y, Rodriguez FJ, Wang L, Perry JSA, et al. Astrocytic trans-differentiation completes a multicellular paracrine feedback loop required for medulloblastoma tumor growth. Cell. 2020;180:502–20.e19.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol. 2012;188:29–36.

    CAS  PubMed  Google Scholar 

  19. Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Investig. 2007;117:902–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gate D, Danielpour M, Rodriguez J Jr, Kim GB, Levy R, Bannykh S, et al. T-cell TGF-beta signaling abrogation restricts medulloblastoma progression. Proc Natl Acad Sci USA. 2014;111:E3458–E66.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tan IL, Wojcinski A, Rallapalli H, Lao Z, Sanghrajka RM, Stephen D, et al. Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation. Proc Natl Acad Sci USA. 2018;115:3392–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Rallapalli H, Tan IL, Volkova E, Wojcinski A, Darwin BC, Lerch JP, et al. MEMRI-based imaging pipeline for guiding preclinical studies in mouse models of sporadic medulloblastoma. Magn Reson Med. 2020;83:214–27.

    PubMed  Google Scholar 

  23. Corcoran RB, Bachar Raveh T, Barakat MT, Lee EY, Scott MP. Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res. 2008;68:8788–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem. 2000;275:28341–4.

    CAS  PubMed  Google Scholar 

  25. Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, Fults DW. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene. 2004;23:6156–62.

    CAS  PubMed  Google Scholar 

  26. Tanori M, Santone M, Mancuso M, Pasquali E, Leonardi S, Di Majo V, et al. Developmental and oncogenic effects of insulin-like growth factor-I in Ptc1+/− mouse cerebellum. Mol Cancer. 2010;9:53.

    PubMed  PubMed Central  Google Scholar 

  27. Wang JY, Del Valle L, Gordon J, Rubini M, Romano G, Croul S, et al. Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas. Oncogene. 2001;20:3857–68.

    CAS  PubMed  Google Scholar 

  28. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Consortium TGO. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47:D330–d338.

    Google Scholar 

  30. Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2019;47:D419–d26.

    CAS  PubMed  Google Scholar 

  31. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Greter M, Lelios I, Croxford AL. Microglia versus myeloid cell nomenclature during brain inflammation. Front Immunol. 2015;6:249.

    PubMed  PubMed Central  Google Scholar 

  34. Kana V, Desland FA, Casanova-Acebes M, Ayata P, Badimon A, Nabel E, et al. CSF-1 controls cerebellar microglia and is required for motor function and social interaction. J Exp Med. 2019;216:2265–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA. 2016;113:E1738–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012;3:51.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356–71.

    CAS  PubMed  Google Scholar 

  39. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68:869–77.

    CAS  PubMed  Google Scholar 

  40. Huang Y, Xu Z, Xiong S, Sun F, Qin G, Hu G, et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci. 2018;21:530–40.

    CAS  PubMed  Google Scholar 

  41. Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc Natl Acad Sci USA. 2018;115:E4041–e50.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.

    CAS  PubMed  Google Scholar 

  43. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gyori D, Lim EL, Grant FM, Spensberger D, Roychoudhuri R, Shuttleworth SJ. et al. Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy. JCI Insight. 2018;3:e120631.

    PubMed Central  Google Scholar 

  45. Celada A, Klemsz MJ, Maki RA. Interferon-gamma activates multiple pathways to regulate the expression of the genes for major histocompatibility class II I-A beta, tumor necrosis factor and complement component C3 in mouse macrophages. Eur J Immunol. 1989;19:1103–9.

    CAS  PubMed  Google Scholar 

  46. Lee C, Lee J, Choi SA, Kim SK, Wang KC, Park SH, et al. M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas. BMC Cancer. 2018;18:535.

    PubMed  PubMed Central  Google Scholar 

  47. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12:818–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Martin AM, Nirschl CJ, Polanczyk MJ, Bell WR, Nirschl TR, Harris-Bookman S, et al. PD-L1 expression in medulloblastoma: an evaluation by subgroup. Oncotarget. 2018;9:19177–91.

    PubMed  PubMed Central  Google Scholar 

  49. Murata D, Mineharu Y, Arakawa Y, Liu B, Tanji M, Yamaguchi M, et al. High programmed cell death 1 ligand-1 expression: association with CD8+ T-cell infiltration and poor prognosis in human medulloblastoma. J Neurosurg. 2018;128:710–6.

    CAS  PubMed  Google Scholar 

  50. Vermeulen JF, Van Hecke W, Adriaansen EJM, Jansen MK, Bouma RG, Villacorta Hidalgo J, et al. Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma. Oncoimmunology. 2018;7:e1398877.

    PubMed  Google Scholar 

  51. Machold R, Fishell G. Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron. 2005;48:17–24.

    CAS  PubMed  Google Scholar 

  52. Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 2006;66:10171–8.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Joyner lab members for helpful discussions and comments on the manuscript. We are grateful to Andrey Rymar and Parmveer Singh at Plexxikon for providing the PLX5622 used in these studies. We appreciate the technical assistance from Daniel Stephen, and Yu-Jung Chen. We also thank the Center for comparative medicine and pathology and the Integrated Genomics Operation (IGO) core facilities of MSKCC for outstanding technical support. This work was supported by the following grants: R01CA192176 (ALJ), MSKCC Brain Tumor Center fellowship (AW), and a National Cancer Institute Cancer Center Support Grant [P30 CA008748-48].

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Tan, IL., Arifa, R.D.N., Rallapalli, H. et al. CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model. Oncogene 40, 396–407 (2021). https://doi.org/10.1038/s41388-020-01536-0

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