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Tumor Immune Microenvironment of Soft Tissue Sarcoma

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Cancer Metastasis Through the Lymphovascular System

Abstract

Soft tissue sarcoma (STS) is a group of cancers transformed from mesenchymal cells. The treatment outcome of immunotherapy has not been as successful in STS, and our understanding of the tumor immune microenvironment (TIME) may help us in the search of better treatment. This chapter aims to describe the tumor immune microenvironment of soft tissue sarcoma in detail in terms of specific immune cell types as well as specific histologies. The topics included B cells and tertiary lymphoid structures, T cells, macrophages, and the effects of anticancer treatments on the TIME. In the latter part of this chapter, we will also discuss about the TIME of leiomyosarcoma, liposarcoma, and epigenetic regulation-associated STS and ways to improve the treatment.

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References

  1. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lee ATJ, Chew W, Wilding CP, et al. The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma. Sci Rep. 2019;9:14602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70:46–58.

    Article  CAS  PubMed  Google Scholar 

  4. Edin S, Kaprio T, Hagstrom J, et al. The prognostic importance of CD20(+) B lymphocytes in colorectal cancer and the relation to other immune cell subsets. Sci Rep. 2019;9:19997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sturm G, Finotello F, Petitprez F, et al. Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology. Bioinformatics. 2019;35:i436–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Finotello F, Rieder D, Hackl H, Trajanoski Z. Next-generation computational tools for interrogating cancer immunity. Nat Rev Genet. 2019;20:724–46.

    Article  CAS  PubMed  Google Scholar 

  7. Cancer Genome Atlas Research Network. Electronic address edsc, Cancer Genome Atlas Research N. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 2017;171:950–965.e928.

    Article  CAS  Google Scholar 

  8. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iglesia MD, Parker JS, Hoadley KA, et al. Genomic analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst. 2016;108:djw144.

    Article  PubMed Central  CAS  Google Scholar 

  10. Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355:eaaf8399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Chen L, Oke T, Siegel N, et al. The immunosuppressive niche of soft-tissue sarcomas is sustained by tumor-associated macrophages and characterized by intratumoral tertiary lymphoid structures. Clin Cancer Res. 2020;26:4018–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dancsok AR, Setsu N, Gao D, et al. Expression of lymphocyte immunoregulatory biomarkers in bone and soft-tissue sarcomas. Mod Pathol. 2019;32:1772–85.

    Article  CAS  PubMed  Google Scholar 

  13. Fujii H, Arakawa A, Utsumi D, et al. CD8(+) tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma. Int J Cancer. 2014;134:2393–402.

    Article  CAS  PubMed  Google Scholar 

  14. Pollack SM, He Q, Yearley JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer. 2017;123:3291–304.

    Article  CAS  PubMed  Google Scholar 

  15. Petitprez F, de Reynies A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577:556–60.

    Article  CAS  PubMed  Google Scholar 

  16. Becht E, Giraldo NA, Lacroix L, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17:218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Buckley CD, Barone F, Nayar S, et al. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol. 2015;33:715–45.

    Article  CAS  PubMed  Google Scholar 

  18. Sautes-Fridman C, Verneau J, Sun CM, et al. Tertiary lymphoid structures and B cells: clinical impact and therapeutic modulation in cancer. Semin Immunol. 2020;48:101406.

    Article  CAS  PubMed  Google Scholar 

  19. Sorbye SW, Kilvaer T, Valkov A, et al. Prognostic impact of lymphocytes in soft tissue sarcomas. PLoS One. 2011;6:e14611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Tsagozis P, Augsten M, Zhang Y, et al. An immunosuppressive macrophage profile attenuates the prognostic impact of CD20-positive B cells in human soft tissue sarcoma. Cancer Immunol Immunother. 2019;68:927–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sautes-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19:307–25.

    Article  CAS  PubMed  Google Scholar 

  22. Lin Q, Tao P, Wang J, et al. Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors. Oncoimmunology. 2020;9:1747339.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yan L, Wang Z, Cui C, et al. Comprehensive immune characterization and T-cell receptor repertoire heterogeneity of retroperitoneal liposarcoma. Cancer Sci. 2019;110(10):3038–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Posch F, Silina K, Leibl S, et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology. 2018;7:e1378844.

    Article  PubMed  Google Scholar 

  25. Martin-Broto J, Moura DS, Van Tine BA. Facts and hopes in immunotherapy of soft-tissue sarcomas. Clin Cancer Res. 2020;26:5801–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. D'Angelo SP, Shoushtari AN, Agaram NP, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46:357–65.

    Article  CAS  PubMed  Google Scholar 

  27. van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, et al. Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8(+) lymphocytes in primary sarcomas is subtype dependent. Oncotarget. 2017;8:71371–84.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial. JAMA Oncol. 2018;4:93–7.

    Article  PubMed  Google Scholar 

  29. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.

    Article  CAS  PubMed  Google Scholar 

  30. Samji T, Khanna KM. Understanding memory CD8(+) T cells. Immunol Lett. 2017;185:32–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Klaver Y, Rijnders M, Oostvogels A, et al. Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes. J Immunother Cancer. 2020;8:e000271.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018;17:887–904.

    Article  CAS  PubMed  Google Scholar 

  34. Dancsok AR, Gao D, Lee AF, et al. Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas. Oncoimmunology. 2020;9:1747340.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shiraishi D, Fujiwara Y, Horlad H, et al. CD163 is required for protumoral activation of macrophages in human and murine sarcoma. Cancer Res. 2018;78:3255–66.

    Article  CAS  PubMed  Google Scholar 

  36. Feng M, Jiang W, Kim BYS, et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19:568–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019;394:478–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14:365–79.

    Article  CAS  PubMed  Google Scholar 

  39. Wisdom AJ, Mowery YM, Hong CS, et al. Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy. Nat Commun. 2020;11:6410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Galluzzi L, Humeau J, Buque A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–41.

    Article  PubMed  Google Scholar 

  41. Ueda T, Kakunaga S, Ando M, et al. Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma. Investig New Drugs. 2014;32:691–9.

    Article  CAS  Google Scholar 

  42. Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 2005;65:2964–71.

    Article  CAS  PubMed  Google Scholar 

  43. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249–62.

    Article  CAS  PubMed  Google Scholar 

  44. Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017;117:628–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wilky BA, Trucco MM, Subhawong TK, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial. Lancet Oncol. 2019;20:837–48.

    Article  CAS  PubMed  Google Scholar 

  46. Martin-Broto J, Hindi N, Grignani G, et al. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. J Immunother Cancer. 2020;8:e001561.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Keung EZ, Burgess M, Salazar R, et al. Correlative analyses of the SARC028 trial reveal an association between sarcoma-associated immune infiltrate and response to pembrolizumab. Clin Cancer Res. 2020;26:1258–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang S, Kohli K, Black RG, et al. Systemic interferon-gamma increases MHC class I expression and T-cell infiltration in cold tumors: results of a phase 0 clinical trial. Cancer Immunol Res. 2019; https://doi.org/10.1158/2326-6066.CIR-18-0940.

  49. Hemming ML, Fan C, Raut CP, et al. Oncogenic gene-expression programs in leiomyosarcoma and characterization of conventional, inflammatory, and uterogenic subtypes. Mol Cancer Res. 2020;18:1302–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee CH, Espinosa I, Vrijaldenhoven S, et al. Prognostic significance of macrophage infiltration in leiomyosarcomas. Clin Cancer Res. 2008;14:1423–30.

    Article  CAS  PubMed  Google Scholar 

  52. Espinosa I, Beck AH, Lee CH, et al. Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1-related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma. Am J Pathol. 2009;174:2347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Espinosa I, Edris B, Lee CH, et al. CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis. Am J Pathol. 2011;179:2100–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A. 2012;109:6656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tseng WW, Malu S, Zhang M, et al. Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma. Sarcoma. 2015;2015:547460.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Burgess MA, Bolejack V, Schuetze S, et al. Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): final results of SARC028 expansion cohorts. J Clin Oncol. 2019;37:11015.

    Article  Google Scholar 

  57. Beird HC, Wu CC, Ingram DR, et al. Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin. Cold Spring Harb Mol Case Stud. 2018;4:a002386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Snow H, Mitchell C, Hendry S, et al. Characterising the immune microenvironment in liposarcoma, its impact on prognosis and the impact of radiotherapy. J Surg Oncol. 2021;123:117–26.

    Article  CAS  PubMed  Google Scholar 

  59. Pollack SM, Jungbluth AA, Hoch BL, et al. NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma. Cancer. 2012;118:4564–70.

    Article  CAS  PubMed  Google Scholar 

  60. Somaiah N, Chawla SP, Block MS, et al. A phase 1b study evaluating the safety, tolerability, and immunogenicity of CMB305, a lentiviral-based prime-boost vaccine regimen, in patients with locally advanced, relapsed, or metastatic cancer expressing NY-ESO-1. Oncoimmunology. 2020;9:1847846.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Casadei L, Calore F, Braggio DA, et al. MDM2 derived from dedifferentiated liposarcoma extracellular vesicles induces MMP2 production from preadipocytes. Cancer Res. 2019;79:4911–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nacev BA, Jones KB, Intlekofer AM, et al. The epigenomics of sarcoma. Nat Rev Cancer. 2020;20(10):608–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46:1227–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012;149:214–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shurell E, Singh AS, Crompton JG, et al. Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes. Oncotarget. 2016;7:64300–8.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Wilson BG, Wang X, Shen X, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010;18:316–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gounder M, Schoffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21:1423–32.

    Article  CAS  PubMed  Google Scholar 

  68. Chun HE, Johann PD, Milne K, et al. Identification and analyses of extra-cranial and cranial rhabdoid tumor molecular subgroups reveal tumors with cytotoxic T cell infiltration. Cell Rep. 2019;29:2338–2354.e2337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Burr ML, Sparbier CE, Chan KL, et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019;36:385–401.e388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhou L, Mudianto T, Ma X, et al. Targeting EZH2 enhances antigen presentation, antitumor immunity, and circumvents Anti-PD-1 resistance in head and neck cancer. Clin Cancer Res. 2020;26:290–300.

    Article  CAS  PubMed  Google Scholar 

  71. Gounder MM, Zhu G, Roshal L, et al. Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative poorly differentiated chordoma after EZH2 inhibition and radiotherapy. Clin Cancer Res. 2019;25:2064–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Tom Wei-Wu Chen & Sheng-Fang Su

  2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Tom Wei-Wu Chen

  3. YongLin Institute of Health, National Taiwan University (National Taiwan University YongLin Scholar), Taipei, Taiwan

    Sheng-Fang Su

  4. Department of Surgery, Division of Breast, Endocrine and Soft Tissue Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

    William W. Tseng

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  1. Tom Wei-Wu Chen
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  2. Sheng-Fang Su
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Correspondence to Tom Wei-Wu Chen .

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Editors and Affiliations

  1. Department of Surgery and Melanoma Center, California Pacific Medical Center and Research Institute, San Francisco, CA, USA

    Stanley P. Leong

  2. Henry Ford Cancer Institute, Detroit, MI, USA

    S. David Nathanson

  3. Moffitt Cancer Center, Tampa, FL, USA

    Jonathan S. Zager

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Chen, T.WW., Su, SF., Tseng, W.W. (2022). Tumor Immune Microenvironment of Soft Tissue Sarcoma. In: Leong, S.P., Nathanson, S.D., Zager, J.S. (eds) Cancer Metastasis Through the Lymphovascular System. Springer, Cham. https://doi.org/10.1007/978-3-030-93084-4_61

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