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Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies

  • Sarcoma (SH Okuno, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The role of targeted therapy is firmly established for gastrointestinal stromal tumors (GISTs); other modalities for targeting this disease are necessary for recurrent and refractory disease. There are several lines of evidence pointing to an active role of the immune system in GIST. Preclinical and clinical studies revealed that the most common type of immune cell infiltration in GISTs is tumor-associated macrophages (TAMs). The mechanism of how TAMs sculpt the tumor microenvironment in GIST is not clear, but it seems that the presence of immunosuppressive regulatory T cells (Tregs) is correlated with the number of TAMs, thus linking macrophages to immunosuppression. CD3+ T cells and NK infiltrates are found in the GIST microenvironment and carry some prognostic value. In early clinical trials, there is evidence for an active role for immunotherapy in treating GIST patients. Moreover, preclinical evidence has indicated that combining TKIs with checkpoint blockers may be synergistic in murine GIST models. Overall, there is substantial preclinical and clinical evidence to support a role for immunoregulation in GIST and further studies will be important for the development of immunotherapies for GIST.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Judson I, Demetri G. Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol. 2007;18(Suppl 10):x20–4.

    Article  PubMed  Google Scholar 

  2. Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3:557–86.

    Article  CAS  PubMed  Google Scholar 

  3. Watson GA, Kelly D, Melland-Smith M, Gleeson J, McEntee G, Kelly CM, et al. Get the GIST? An overview of gastrointestinal stromal tumours. Ir J Med Sci. 2016;185(2):319–26.

    Article  CAS  PubMed  Google Scholar 

  4. Soreide K, Sandvik OM, Soreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 2016;40:39–46.

    Article  PubMed  Google Scholar 

  5. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science (New York, NY). 1998;279(5350):577–80.

    Article  CAS  Google Scholar 

  6. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152(5):1259–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol. 1998;11(8):728–34.

    CAS  PubMed  Google Scholar 

  8. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol. 1999;154(1):53–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96(3):925–32.

    Article  CAS  PubMed  Google Scholar 

  10. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344(14):1052–6.

    Article  CAS  PubMed  Google Scholar 

  11. Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20(36):5054–8.

    Article  CAS  PubMed  Google Scholar 

  12. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, et al. NCCN task force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Cancer Netw. 2007;5(Suppl 2):S1–29 quiz S30.

  13. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231(1):51–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blanke CD, Rankin C, Demetri GD, Ryan CW, Von Mehren M, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626–32.

    Article  CAS  PubMed  Google Scholar 

  15. Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–80.

    Article  CAS  PubMed  Google Scholar 

  16. van Oosterom AT, Judson I, Verweij J, Stroobants S, di Paola ED, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358(9291):1421–3.

    Article  PubMed  Google Scholar 

  17. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay J-Y, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127–34.

    Article  CAS  PubMed  Google Scholar 

  18. Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, et al. Correlation of kinase genotype and clinical outcome in the North American intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26(33):5360–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Serrano C, Vivancos A, Lopez-Pousa A, Matito J, Mancuso FM, Valverde C, et al. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors. BMC Cancer. 2020;20(1):99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smith BD, Kaufman MD, Lu WP, Gupta A, Leary CB, Wise SC, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738–51 e9.

  21. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302.

    Article  CAS  PubMed  Google Scholar 

  22. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.

    Article  CAS  PubMed  Google Scholar 

  23. Szucs Z, Thway K, Fisher C, Bulusu R, Constantinidou A, Benson C, et al. Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol (London, England). 2017;13(1):93–107.

    Article  CAS  Google Scholar 

  24. Smith BD, Kaufman MD, Lu W-P, Gupta A, Leary CB, Wise SC, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738–51 e9.

  25. Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med. 2017;9(414).

  26. D'Angelo SP, Shoushtari AN, Keohan ML, Dickson MA, Gounder MM, Chi P, et al. Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: a phase Ib study of dasatinib plus ipilimumab. Clin Cancer Res. 2017;23(12):2972–80.

    Article  CAS  PubMed  Google Scholar 

  27. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, et al. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. 2014;122:91–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000;88(3):577–83.

    Article  CAS  PubMed  Google Scholar 

  29. Deng L, Stafford JH, Liu S-C, Chernikova SB, Merchant M, Recht L, et al. SDF-1 blockade enhances anti-VEGF therapy of glioblastoma and can be monitored by MRI. Neoplasia. 2017;19(1):1–7.

    Article  PubMed  CAS  Google Scholar 

  30. Ferrara N. Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr Opin Hematol. 2010;17(3):219–24.

    CAS  PubMed  Google Scholar 

  31. 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(18):5057–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu S-C, Alomran R, Chernikova SB, Lartey F, Stafford J, Jang T, et al. Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats. Neuro-oncology. 2013;16(1):21–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Brown JM, Recht L, Strober S. The promise of targeting macrophages in cancer therapy. Clin Cancer Res. 2017;23(13):3241–50.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Florou V, Wilky BA, Trent JC. Latest advances in adult gastrointestinal stromal tumors. Future Oncol. 2017;13(24):2183–93.

    Article  CAS  PubMed  Google Scholar 

  35. Tan Y, Trent J, Wilky BA, Kerr D, Rosenberg A. Current status of immunotherapy for gastrointestinal stromal tumor. Cancer Gene Ther. 2017;24(3):130–3.

    Article  CAS  PubMed  Google Scholar 

  36. Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, et al. PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2017;23(2):454–65 This study showed an important clinical and preclinical evidence of immunotherapy in GIST.

    Article  CAS  PubMed  Google Scholar 

  37. Cameron S, Gieselmann M, Blaschke M, Ramadori G, Füzesi L. Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST). Int J Clin Exp Pathol. 2014;7(7):3563–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. van Dongen M, Savage ND, Jordanova ES, Briaire-de Bruijn IH, Walburg KV, Ottenhoff TH, et al. Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int J Cancer. 2010;127(4):899–909.

    PubMed  Google Scholar 

  39. Rusakiewicz S, Semeraro M, Sarabi M, Desbois M, Locher C, Mendez R, et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 2013;73(12):3499–510.

    Article  CAS  PubMed  Google Scholar 

  40. Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, et al. Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br J Surg. 2016;103(7):845–54.

    Article  CAS  PubMed  Google Scholar 

  41. Diana A, Wang LM, D'Costa Z, Allen P, Azad A, Silva MA, et al. Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget. 2016;7(27):40992–1004.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Blakely AM, Matoso A, Patil PA, Taliano R, Machan JT, Miner TJ, et al. Role of immune microenvironment in gastrointestinal stromal tumours. Histopathology. 2018;72(3):405–13 Important literature that provided immunological phenomenon in GIST tumor.

    Article  PubMed  Google Scholar 

  43. Pantaleo MA, Tarantino G, Agostinelli C, Urbini M, Nannini M, Saponara M, et al. Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response. Oncoimmunology. 2019;8(9):e1617588.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lim SH, Chua W, Cheng C, Descallar J, Ng W, Solomon M, et al. Effect of neoadjuvant chemoradiation on tumor-infiltrating/associated lymphocytes in locally advanced rectal cancers. Anticancer Res. 2014;34(11):6505–13.

    CAS  PubMed  Google Scholar 

  45. Hodge G, Barnawi J, Jurisevic C, Moffat D, Holmes M, Reynolds P, et al. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells. Clin Exp Immunol. 2014;178(1):79–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tan Y, Garcia-Buitrago MT, Trent JC, Rosenberg AE. The immune system and gastrointestinal stromal tumor: a wealth of opportunities. Curr Opin Oncol. 2015;27(4):338–42.

    Article  CAS  PubMed  Google Scholar 

  47. Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011;17(6):700–7.

    Article  CAS  PubMed  Google Scholar 

  48. Bertucci F, Finetti P, Mamessier E, Pantaleo MA, Astolfi A, Ostrowski J, et al. PDL1 expression is an independent prognostic factor in localized GIST. Oncoimmunology. 2015;4(5):e1002729 This original article revealed important immunological markers for localized GIST.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science (New York, NY). 2018;362(6411):eaar3593.

    Article  CAS  Google Scholar 

  50. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Swigart LB, et al. Myc cooperates with Ras by programming inflammation and immune suppression. Cell. 2017;171(6):1301–15 e14.

  52. Topper MJ, Vaz M, Chiappinelli KB, Shields CED, Niknafs N, Yen R-WC, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell. 2017;171(6):1284–300 e21.

  53. Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, et al. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Invest. 2019; This article provided the asscociation between mutational status and immune markers for GIST.

  54. Borg C, Terme M, Taïeb J, Ménard C, Flament C, Robert C, et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects. J Clin Invest. 2004;114(3):379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen LL, Chen X, Choi H, Sang H, Chen LC, Zhang H, et al. Exploiting antitumor immunity to overcome relapse and improve remission duration. Cancer Immunol Immunother. 2012;61(7):1113–24.

    Article  CAS  PubMed  Google Scholar 

  56. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17(9):1094 This article showed the influence of imatinib as a standard TKI on the immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Toulmonde M, Penel N, Adam J, Chevreau C, Blay JY, Le Cesne A, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial. JAMA Oncol. 2018;4(1):93–7 Targeting of macrophage as a novel concept for immunotherapy in sarcoma including GIST.

    Article  PubMed  Google Scholar 

  58. Singh AS, Chmielowski B, Hecht JR, Rosen LS, Wang X, Brackert S, et al. A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST). J Clin Oncol. 2018;36(4_suppl):55.

    Article  Google Scholar 

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Acknowledgments

The authors thank the Information Technology Center, University of California, Los Angeles.

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Authors and Affiliations

  1. Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA, USA

    Jomjit Chantharasamee MD, Karlton Wong MD, MSG, Bartosz Chmielowski MD, PhD & Arun S. Singh MD

  2. Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Jomjit Chantharasamee MD

  3. Department of Internal Medicine, University of South Florida, H. Lee Moffit Cancer Center, Tampa, FL, USA

    Jacob J. Adashek DO

  4. Department of Surgery, Yale School of Medicine, New Haven, CT, USA

    Mark A. Eckardt MD

  5. Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA, USA

    Mark A. Eckardt MD & Fritz C. Eilber MD, MPH

  6. UCLA–JCCC Sarcoma Program, Los Angeles, CA, USA

    Bartosz Chmielowski MD, PhD, Sarah Dry MD, PhD & Fritz C. Eilber MD, MPH

  7. Department of Pathology, University of California Los Angeles, Los Angeles, CA, USA

    Sarah Dry MD, PhD & Arun S. Singh MD

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Correspondence to Arun S. Singh MD.

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Conflict of Interest

Jomjit Chantharasamee declares that he has no conflict of interest. Jacob J. Adashek declares that he has no conflict of interest. Karlton Wong declares that he has no conflict of interest. Mark A. Eckardt declares that he has no conflict of interest. Bartosz Chmielowski has received compensation for service on advisory boards from IDEAYA Biosciences, Biothera, Epizyme, Deciphera, Iovance Biotherapeutics, Sanofi Genzyme, Regeneron, Eli Lilly, HUYA Bioscience International, Compugen, Array BioPharma, and Merck and has received compensation for service on speakers’ bureaus from Sanofi Genzyme, Regeneron, Janssen, and Genentech. Sarah Dry declares that she has no conflict of interest. Fritz C. Eilber has served on a scientific advisory board for Certis Oncology Solutions. Arun S. Singh has received research support from Bristol-Myers Squibb (grant and provided drug for trial), Eli Lilly, Daiichi Sankyo, Deciphera, NanoCarrier, Eisai, and Blueprint Medicines; has received compensation from Bristol-Myers Squibb, Eli Lilly, Novartis, Daiichi Sankyo, Deciphera, Expert Perspectives, OncLive, Roche, and Blueprint Medicines; and serves on the board of directors and owns stock in Certis Oncology Solutions.

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Chantharasamee, J., Adashek, J.J., Wong, K. et al. Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies. Curr. Treat. Options in Oncol. 22, 9 (2021). https://doi.org/10.1007/s11864-020-00806-z

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