breast cancer: innocent bystander or important player?
CONCLUSIONS AND FUTURE PERSPECTIVES
Collectively, many preclinical studies illustrated the protumor function of TAMs in breast cancer. TAMs play a role in tumor growth, progression, treatment resistance and immune suppression. However, the clinical efficacy of targeting TAMs in breast cancer so far has been limited. Potential options to improve this include combination strategies. Particularly in view of the immunosuppressive role of TAMs in the breast cancer microenvironment, results of clinical trials combining TAM targeting and checkpoint inhibition are eagerly awaited.
First results of anti-CSF1R antibody cabiralizumab and anti-PD-1 antibody nivolumab combination showed a tolerable safety profile and four partial responses in 31 patients with advanced pancreatic cancer.105 Data on clinical efficacy of TAM-targeted therapies in patients with breast cancer is limited. A careful approach in targeting the total population monocytes or macrophages is needed, for example classical CD14+CD16−CD33+HLA-DRhi monocytes may be beneficial to obtain a response to immunotherapy.106 Also strategies combining TAM-targeted agents with chemotherapy, radiotherapy or HER2 targeted drugs may induce synergistic therapeutic effects. Additional macrophage-targeted agents, are currently being evaluated in other cancer types (Table S2).
To improve targeting TAMs, also a number of challenges need to be addressed. For some targets such as CD47, the effect is probably not solely mediated by TAMs. Some drugs such as CSF1R tyrosine kinase inhibitor pexidartinib target more tyrosine kinases, which makes it difficult to study the contribution of targeting TAMs on its antitumor effect.6 Improving insight in these interactions can potentially improve these intervention strategies. This is of particular importance when considering for instance resistance to macrophage-targeted therapy involving cross talk between TAMs and other cells. This was described in a recent study, demonstrating that tumor-associated fibroblasts impaired the antitumor effects of a CSF1R inhibitor.107 Furthermore, the timing of the anti-TAM treatment may influence results of TAM targeting treatments, especially regarding combination strategies. For instance, the increasing awareness of macrophage activation syndrome after T cell-engaging therapies, which is characterized by severe immune activation and immune mediated multiple organ failure, may call for upfront macrophage-directed therapies in this setting, such as IL-6 blockade.108
To improve TAM directed therapy, monitoring whole body TAM dynamics and phenotype upon TAM targeting therapy is crucial. Techniques such as molecular imaging might provide whole body insight in macrophages populations, heterogeneity (between primary and metastatic tumors), and pharmacodynamics. This approach has been tested preclinically using imaging modalities such as a radiolabeled nanobody PET tracer targeting M2 marker CD206.109 Clinically, the FDA and EMA approved imaging agent Lymphoseek (99mTc-tilmanocept) targeting CD206 has been used for lymphatic mapping in sentinel lymph node biopsy in multiple cancer types, including breast cancer.110
7
TUMOR-ASSOCIATED MACROPHAGES IN BREAST CANCER: INNOCENT BYSTANDER OR IMPORTANT PLAYER?
143 REFERENCES
1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108.
2. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39-51.
3. Belli C, Trapani D, Viale G, et al. Targeting the microenvironment in solid tumors. Cancer Treat Rev. 2018;65:22-32.
4. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49-61.
5. Xu M, Liu M, Du X, et al. Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype. J Immunol. 2015;194:4997-5006.
6. DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1:54-67.
7. Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM. TH2-polarized CD4(+) T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res. 2015;3:518-25.
8. Zhang Q, Liu L, Gong C, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7:e50946.
9. Altman DG, McShane LM, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies (REMARK):explanation and elaboration. PLoS Med. 2012;9:e1001216.
10. Bain CC, Scott CL, Uronen-Hansson H, et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C hi monocyte precursors. Mucosal Immunol. 2013;6:498-510.
11. Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399-416.
12. Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol. 2008;84:623-30.
13. Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science.
2014;344:921-5.
14. Martinez FO, Gordon S, Locati M, et al. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303-11.
15. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958-69.
16. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-55.
17. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.
Nat Immunol. 2010;11:889-96.
18. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.
19. Aras S, Raza Zaidi M. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer.
2017;117:1583-91.
20. Sousa S, Brion R, Lintunen M, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 2015;17:101.
21. Su S, Liu Q, Chen J, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25:605-20.
22. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462-72.
23. Mahmoud SMA, Lee AHS, Paish EC, et al. Tumour-infiltrating macrophages and clinical outcome in breast cancer.
J Clin Pathol. 2012;65:159-63.
24. Yuan Z-Y, Luo R-Z, Peng R-J, et al. High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. Onco Targets Ther. 2014;7:1475-80.
25. Tiainen S, Tumelius R, Rilla K, et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology. 2015;66:873-83.
26. Liu H, Wang J, Liu Z, et al. Jagged1 modulated tumor-associated macrophage differentiation predicts poor prognosis in patients with invasive micropapillary carcinoma of the breast. Med. 2017;96:e6663.
27. Gwak JM, Jang MH, Kim D Il, et al. Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One. 2015;10:1-14.
28. Mohammed ZM, Going JJ, Edwards J, et al. The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2012;107:864-73.
29. Zhang W, Wang X, Gao S, et al. Tumor-associated macrophages correlate with phenomenon of epithelial-mesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients. J Surg Res.
2018;222:93-101.
30. Klingen TA, Chen Y, Aas H, et al. Tumor-associated macrophages are strongly related to vascular invasion,
non-luminal subtypes, and interval breast cancer. Hum Pathol. 2017;69:72-80.
31. Ali HR, Chlon L, Pharoah PDP, et al. Patterns of immune infiltration in breast cancer and their clinical implications:
a gene-expression-based retrospective study. PLoS Med. 2016;13:e1002194.
32. Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2017;109:1-9.
33. Gottfried E, Kunz-Schughart LA, Weber A, et al. Expression of CD68 in non-myeloid cell types. Scand J Immunol.
2008;67:453-63.
34. Ambarus CA, Krausz S, van Eijk M, et al. Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J Immunol Methods. 2012;375:196-206.
35. Georgoudaki AM, Prokopec KE, Boura VF, et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 2016;15:2000-11.
36. Koru-Sengul T, Santander AM, Miao F, et al. Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians. Breast Cancer Res Treat. 2016;158:113-26.
37. Miyasato Y, Shiota T, Ohnishi K, et al. The high density of CD204-positive macrophages predicts worse clinical prognosis in patients with breast cancer. Cancer Sci. 2017;108:1693-700.
38. Yuan X, Zhang J, Li D, et al. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol Oncol. 2017;147:181-7.
39. Carron EC, Homra S, Rosenberg J, et al. Macrophages promote the progression of premalignant mammary lesions to invasive cancer. Oncotarget. 2017;8:50731-46.
40. Aharinejad S, Paulus P, Sioud M, et al. Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res. 2004;64:5378-84.
41. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin.
Cancer Cell. 2013;23:249-62.
42. Li H, Yang B, Huang J, et al. Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells. Oncotarget. 2015;6:29637-50.
43. Muthuswamy R, Okada NJ, Jenkins FJ, et al. Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues. Brain Behav Immun. 2017;62:78-86.
44. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239-52.
45. Sangaletti S, Di Carlo E, Gariboldi S, et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 2008;68:9050-9.
46. Chen J, Yao Y, Gong C, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541-55.
47. Wyckoff J, Wang W, Lin EY, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 2004;64:7022-9.
48. Su S, Liao J, Liu J, et al. Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer.
Cell Res. 2017;27:461-82.
49. Trikha P, Sharma N, Pena C, et al. E2f3 in tumor macrophages promotes lung metastasis. Oncogene. 2016;35:3636-50. Harney AS, Arwert EN, Entenberg D, et al. Real-time imaging reveals local, transient vascular permeability, and 46.
tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 2015;5:932-43.
51. Harney AS, Karagiannis GS, Pignatelli J, et al. The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol Cancer Ther. 2017;16:2486-52. Mazzieri R, Pucci F, Moi D, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing 501.
angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19:512-26.
53. Linde N, Casanova-Acebes M, Sosa MS, et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun. 2018;9:21.
54. Qian B, Deng Y, Im JH, et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009;4:e6562.
55. Qian B, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast tumour metastasis. Nature.
2011;475:222-5.
56. Kitamura T, Qian B-Z, Soong D, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015;212:1043-59.
57. Kersten K, Coffelt SB, Hoogstraat M, et al. Mammary tumor-derived CCL2 enhances pro-metastatic systemic
7
TUMOR-ASSOCIATED MACROPHAGES IN BREAST CANCER: INNOCENT BYSTANDER OR IMPORTANT PLAYER?
145
inflammation through upregulation of IL1β in tumor-associated macrophages. Oncoimmunology. 2017;6:e1334744.
58. Qian B-Z, Zhang H, Li J, et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med. 2015;212:1433-48.
59. Mathsyaraja H, Thies K, Taffany D a, et al. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene. 2015;34:3651-61.
60. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med.
2015;212:435-45.
61. Shree T, Olson OC, Elie BT, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 2011;25:2465-79.
62. Olson OC, Kim H, Quail DF, et al. Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep. 2017;19:101-13.
63. Paulus P, Stanley ER, Schäfer R, et al. Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res. 2006;66:4349-56.
64. Yang C, He L, He P, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol. 2015;32:352.
65. Guerriero JL, Sotayo A, Ponichtera HE, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017;543:428-32.
66. Ager EI, Kozin S V., Kirkpatrick ND, et al. Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy. J Natl Cancer Inst. 2015;107:1-12.
67. Dewan MZ, Vanpouille-Box C, Kawashima N, et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin Cancer Res. 2012;18:6668-78.
68. Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39-51.
69. Park S, Jiang Z, Mortenson ED, et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell. 2010;18:160-70.
70. Xu M, Du X, Liu M, et al. The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody. Protein Cell. 2012;3:441-9.
71. Willingham SB, Volkmer J-P, Gentles AJ, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA. 2012;109:6662-7.
72. Weiskopf K, Ring AM, Ho CCM, et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science. 2013;341:88-91.
73. Shi Y, Fan X, Deng H, et al. Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcγ receptors on macrophages. J Immunol. 2015;194:4379-86.
74. Zhao XW, van Beek EM, Schornagel K, et al. CD47-signal regulatory protein-a (SIRPa) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci USA. 2011;108:18342-7.
75. Xu MM, Pu Y, Han D, et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity. 2017;47:363-373.e5.
76. Arlauckas SP, Garris CS, Kohler RH, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017;9:eaal3604.
77. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495-9.
78. Zhu Y, Knolhoff BL, Meyer MA, 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.
79. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612-6.
80. Zippelius A, Schreiner J, Herzig P, et al. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3:236-44.
81. Ma HS, Torres ER, Christmas B, et al. Combination agonist and antagonist antibody therapy enhances vaccine induced T cell responses in non-immunogenic cancers [abstract]. Cancer Res. 2017;77(13, suppl):2613.
82. Bose N, Jonas A, Qiu X, et al. Imprime PGG treatment enhances antibody-dependent cellular phagocytosis (ADCP) of tumor cells by monocyte-derived macrophages [abstract]. Cancer Immunol Res. 2016;4(1, suppl):A015.
83. Chan AS, Qiu X, Jonas A, et al. Imprime PGG, a yeast β-glucan immunomodulator, has the potential to repolarize human monocyte-derived M2 macrophages to M1 phenotype [abstract]. J Immunother Cancer. 2014;2(3, suppl):P191.
84. Bose N, Gorden K, Chan A, et al. Innate immune modulation: The novel immunotherapeutic Imprime PGG triggers the anti-cancer immunity cycle in concert with tumor-targeting, anti-angiogenic and checkpoint inhibitor antibodies
[abstract]. Cancer Immunol Res. 2017;5(3, suppl):B29.
85. Bendell JC, Tolcher AW, Jones SF, et al. A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers [abstract]. Mol Cancer Ther. 2014;12(11, suppl):A252.
86. Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846-59.
87. Querfeld C, Thompson J, Taylor M, et al. A single direct intratumoral injection of TTI-621 (SIRPαFc) induces antitumor activity in patients with relapsed/refractory mycosis fungoides and Sézary syndrome: preliminary findings employing an immune checkpoint inhibitor blocking the CD47 “do not eat” [abstract]. Blood. 2017;130(1, suppl):4076.
88. Rüter J, Antonia SJ, Burris HA, et al. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther. 2010;10:983-93.
89. Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25:876-83.
90. Thomas M, Sadjadian P, Kollmeier J, et al. A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer. Invest New Drugs. 2017;35:345-58.
91. Uhlik MT, Harrison B, Gorden K, et al. Imprime PGG, a soluble yeast β-glucan PAMP, in combination with pembrolizumab induces infiltration and activation of both innate and adaptive immune cells within tumor sites in melanoma and triple-negative breast cancer (TNBC) patients [abstract]. Cancer Res. 2018;78(13, suppl):LB-129.
92. Adams S, Kozhaya L, Martiniuk F, et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012;18:6748-57.
93. Vatner R, Demaria S, Fenton-Kerimian M, et al. Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiation therapy in the treatment of metastatic breast cancer involving the skin or chest wall [abstract].
Int J Radiat Oncol Biol Phys. 2013;87(2, suppl):271.
94. Geller MA, Cooley S, Argenta PA, et al. Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol Immunother.
2010;59:1877-84.
95. Bonapace L, Coissieux MM, Wyckoff J, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature. 2014;515:130-3.
96. Lim SY, Yuzhalin AE, Gordon-Weeks AN, et al. Targeting the CCL2-CCR2 signaling axis in cancer metastasis.
Oncotarget. 2016;7:28697-710.
97. Diéras V, Wildiers H, Jassem J, et al. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.
Breast. 2015;24:182-90.
98. Kaufman PA, Freyer G, Kemeny M, et al. A phase 1b study of trebananib plus paclitaxel (P) and trastuzumab (T) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC) [abstract]. J Clin Oncol. 2014;32(15, suppl):502.
99. 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.
100. Goldstein LJ, Gurtler J, Del Prete SA, et al. Trabectedin as a single-agent treatment of advanced breast cancer after anthracycline and taxane treatment: a multicenter, randomized, phase II study comparing 2 administration regimens. Clin Breast Cancer. 2014;14:396-404.
101. Blum JL, Gonçalves A, Efrat N, et al. A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat. 2016;155:295-302.
102. Rogers TL, Holen I. Tumour macrophages as potential targets of bisphosphonates. J Transl Med. 2011;9:177.
103. Brandão RD, Veeck J, van de Vijver KK, et al. A randomised controlled phase II trial of pre- operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer. Breast Cancer Res. 2013;15:R29.
104. Stasinopoulos I, Shah T, Penet MF, et al. COX-2 in cancer: Gordian knot or Achilles heel? Front Pharmacol.
2013;4:34.
105. Wainberg Z, Piha-Paul S, Luke J, et al. First-in-human phase 1 dose escalation and expansion of a novel combination, anti-CSF-1 receptor (cabiralizumab) plus anti-PD-1 (nivolumab), in patients with advanced solid tumors [abstract].
J Immunother Cancer. 2017;5(3, suppl):O42.
106. Krieg C, Nowicka M, Guglietta S, et al. High-dimensional single-cell analysis predicts response to anti-PD-1
7
TUMOR-ASSOCIATED MACROPHAGES IN BREAST CANCER: INNOCENT BYSTANDER OR IMPORTANT PLAYER?
147
immunotherapy. Nat Med. 2018;24:144-53.
107. Kumar V, Donthireddy L, Marvel D, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell. 2017;32:654-668.e5.
108. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy-assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47-62.
109. Blykers A, Schoonooghe S, Xavier C, et al. PET Imaging of macrophage mannose receptor-expressing macrophages in tumor stroma using 18F-radiolabeled camelid single-domain antibody fragments. J Nucl Med. 2015;56:1265-71.
110. Surasi DS, O’Malley J, Bhambhvani P. 99mTc-Tilmanocept: a novel molecular agent for lymphatic mapping and sentinel lymph node localization. J Nucl Med Technol. 2015;43:87-91.
ACKNOWLEDGMENTS
We would like to thank Karin de Visser (NKI) for her helpful advice. This work was supported by The Abel Tasman Talent Program (ATTP) of the University of Groningen to S. Qiu and by Dutch Cancer Society grant RUG 2010-4739 to C.P. Schröder.