Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

B7-H1 Antigen* ; Tumor-Associated Macrophages*/immunology ; Urinary Bladder Neoplasms*/pathology ; T-Lymphocytes, Regulatory*/immunology; Humans ; Muscles/pathology ; Prognosis ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment

Introduction and Objective: Muscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy.
Methods: We performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC.
Results: High concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8-40.5; p < 0.001) and high concentrations of Tregs were associated with decreased risk of death (HR 0.1, 95% CI 0.01-0.7; p = 0.03) in the multivariate Cox-regression model adjusting for adjuvant chemotherapy, tumor and lymph node stage. Patients in the macrophage rich cluster (2) showed the worst OS with and without adjuvant chemotherapy. The Treg rich cluster (1) showed high levels of effector and proliferating immune cells and had the best survival. Cluster 1 and 2 both were rich in PD-1 and PD-L1 expression on tumor and immune cells.
Conclusion: Treg and macrophage concentrations in MIBC are independent predictors of prognosis and are important players in the TME. Standard IHC with CD163 for macrophages is feasible to predict prognosis but validation to use immune-cell infiltration, especially to predict response to systemic therapies, is required.
(© 2023. The Author(s).)

Nature. 2018 Feb 22;554(7693):544-548. (PMID: 29443960)
Cells. 2021 Jan 15;10(1):. (PMID: 33467469)
Lancet. 2016 May 7;387(10031):1909-20. (PMID: 26952546)
PLoS One. 2012;7(12):e51862. (PMID: 23251644)
Nature. 2021 Jul;595(7867):432-437. (PMID: 34135506)
Front Immunol. 2021 Jan 29;11:615091. (PMID: 33584702)
Turk J Biol. 2021 Oct 18;45(5):624-632. (PMID: 34803459)
Front Med (Lausanne). 2022 Jun 16;9:875142. (PMID: 35783619)
Urol Oncol. 2014 Aug;32(6):791-7. (PMID: 24794251)
J Immunother Cancer. 2020 May;8(1):. (PMID: 32448798)
Cancer Res. 2015 Sep 1;75(17):3479-91. (PMID: 26269531)
Cancer Immunol Res. 2019 Jun;7(6):923-938. (PMID: 30988029)
Cancers (Basel). 2021 Sep 21;13(18):. (PMID: 34572939)
Lancet Oncol. 2017 Mar;18(3):312-322. (PMID: 28131785)
Nat Med. 2019 Nov;25(11):1706-1714. (PMID: 31686036)
Clin Cancer Res. 2018 Jul 1;24(13):3069-3078. (PMID: 29514839)
Nat Rev Clin Oncol. 2017 Jul;14(7):399-416. (PMID: 28117416)
Cancer Immunol Immunother. 2023 Jan;72(1):137-149. (PMID: 35771253)
Trends Cell Biol. 2015 Apr;25(4):198-213. (PMID: 25540894)
J Immunol. 2017 Oct 1;199(7):2191-2193. (PMID: 28923980)
J Immunother Cancer. 2017 Jul 18;5(1):53. (PMID: 28716061)
CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338)
Nat Commun. 2018 Sep 20;9(1):3826. (PMID: 30237493)
Eur Urol. 2020 Apr;77(4):420-433. (PMID: 31563503)
Clin Cancer Res. 2012 Jun 15;18(12):3377-86. (PMID: 22553347)
Cancer Cell. 2014 Feb 10;25(2):152-65. (PMID: 24525232)
Eur J Immunol. 2007 Jan;37(1):129-38. (PMID: 17154262)
Cancers (Basel). 2021 May 12;13(10):. (PMID: 34066058)
Annu Rev Physiol. 2017 Feb 10;79:541-566. (PMID: 27813830)
Ann Surg Oncol. 2022 Apr;29(4):2495-2503. (PMID: 35000080)
Sci Rep. 2017 Dec 4;7(1):16878. (PMID: 29203879)
Mol Oncol. 2020 Oct;14(10):2384-2402. (PMID: 32671911)
Eur Urol Oncol. 2022 Apr;5(2):203-213. (PMID: 35227680)
Lancet Oncol. 2021 Apr;22(4):525-537. (PMID: 33721560)
Clin Cancer Res. 2020 Feb 15;26(4):882-891. (PMID: 31712383)
Cell Rep. 2018 May 1;23(5):1448-1460. (PMID: 29719257)
J Urol. 2017 Dec;198(6):1253-1262. (PMID: 28668287)
Urol Oncol. 2022 Feb;40(2):63.e19-63.e26. (PMID: 34420870)
Cell. 2017 Oct 19;171(3):540-556.e25. (PMID: 28988769)
Cancer Immunol Immunother. 2019 Dec;68(12):2067-2080. (PMID: 31720813)
Clin Cancer Res. 2012 Jul 15;18(14):3762-71. (PMID: 22645050)
Clin Transl Med. 2020 Dec;10(8):e239. (PMID: 33377644)
Sci Rep. 2015 Oct 14;5:15179. (PMID: 26462617)
N Engl J Med. 2021 Jun 3;384(22):2102-2114. (PMID: 34077643)
Front Cell Dev Biol. 2020 Feb 11;8:17. (PMID: 32117960)
Int Immunol. 2007 Apr;19(4):345-54. (PMID: 17329235)
N Engl J Med. 2017 Mar 16;376(11):1015-1026. (PMID: 28212060)
Eur Urol. 2021 Jan;79(1):82-104. (PMID: 32360052)
Nat Commun. 2020 Sep 25;11(1):4858. (PMID: 32978382)
Oncol Rep. 2019 Aug;42(2):581-594. (PMID: 31233191)
BJU Int. 2011 Nov;108(10):1672-8. (PMID: 21244603)
J Transl Med. 2009 Oct 22;7:89. (PMID: 19849846)
J Immunother Cancer. 2022 Mar;10(3):. (PMID: 35338085)
Sci Transl Med. 2018 Apr 11;10(436):. (PMID: 29643229)
PLoS One. 2013 Nov 15;8(11):e80908. (PMID: 24260507)
World J Urol. 2016 Feb;34(2):181-7. (PMID: 26055646)
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3110-5. (PMID: 24520177)

Keywords: Bladder cancer; Chemotherapy; Immune cells; MIBC; TAM; Treg

0 (B7-H1 Antigen)
0 (Programmed Cell Death 1 Receptor)

Date Created: 20230216 Date Completed: 20230217 Latest Revision: 20230301

20230301

PMC9930232

10.1186/s12967-023-03949-3

36793050