Top

Published in:

01-01-2015 | Focussed Research Review

Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies

Authors: Chiara Castelli, Licia Rivoltini, Monica Rodolfo, Marcella Tazzari, Cristina Belgiovine, Paola Allavena

Published in: Cancer Immunology, Immunotherapy | Issue 1/2015

Abstract

Targeted therapies were rationally designed to inhibit molecular pathways in tumor cells critically involved in growth and survival; however, many drugs used in targeted therapies may affect the immune system. In addition, selected conventional chemotherapeutic agents have also been reported to be endowed with direct or indirect effects on immunity, for instance via immunogenic death of tumors. Thus, cancer therapies may have off-target effects, some of which are directed to the immune system. Here, we will review some of these effects in specific therapeutic approaches. We will examine the modulation of the immune contexture in human sarcoma and melanoma induced by anti-angiogenic therapies and by BRAF inhibitors, respectively. We will then discuss how the anti-tumor agent trabectedin is selectively cytotoxic to cells of the monocytic-macrophage lineage and how these immune-related effects can be part of the response to treatment.

Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G (2013) Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39:74–88PubMedCrossRef

Menard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, Nonn C, Chaput N, Taieb J, Delahaye NF, Flament C, Emile JF, Le Cesne A, Zitvogel L (2009) Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res 69:3563–3569PubMedCrossRef

Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, DeMatteo RP (2011) Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 17:1094–1100PubMedCentralPubMedCrossRef

Cavnar MJ, Zeng S, Kim TS, Sorenson EC, Ocuin LM, Balachandran VP, Seifert AM, Greer JB, Popow R, Crawley MH, Cohen NA, Green BL, Rossi F, Besmer P, Antonescu CR, DeMatteo RP (2013) KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med 210:2873–2886PubMedCentralPubMedCrossRef

Galluzzi L, Senovilla L, Zitvogel L, Kroemer G (2012) The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 11:215–233PubMedCrossRef

Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061PubMedCrossRef

Annels NE, Shaw VE, Gabitass RF, Billingham L, Corrie P, Eatock M, Valle J, Smith D, Wadsley J, Cunningham D, Pandha H, Neoptolemos JP, Middleton G (2014) The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother 63:175–183PubMedCrossRef

Takahashi S (2011) Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 34:1785–1788PubMedCrossRef

Chung AS, Ferrara N (2011) Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol 27:563–584PubMedCrossRef

10.

Dirkx AE, Oude Egbrink MG, Kuijpers MJ, van der Niet ST, Heijnen VV, Bouma-ter Steege JC, Wagstaff J, Griffioen AW (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63:2322–2329PubMed

11.

Griffioen AW, Damen CA, Mayo KH, Barendsz-Janson AF, Martinotti S, Blijham GH, Groenewegen G (1999) Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. Int J Cancer 80:315–319PubMedCrossRef

12.

Johnson BF, Clay TM, Hobeika AC, Lyerly HK, Morse MA (2007) Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther 7:449–460PubMedCrossRef

13.

Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRef

14.

Castelli C, Tazzari M, Negri T, Vergani B, Rivoltini L, Stacchiotti S, Pilotti S (2013) Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma. J Transl Med 11:237PubMedCentralPubMedCrossRef

15.

Lazar AJ, Das P, Tuvin D, Korchin B, Zhu Q, Jin Z, Warneke CL, Zhang PS, Hernandez V, Lopez-Terrada D, Pisters PW, Pollock RE, Lev D (2007) Angiogenesis-promoting gene patterns in alveolar soft part sarcoma. Clin Cancer Res 13:7314–7321PubMedCrossRef

16.

Stacchiotti S, Negri T, Zaffaroni N, Palassini E, Morosi C, Brich S, Conca E, Bozzi F, Cassinelli G, Gronchi A, Casali PG, Pilotti S (2011) Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol 22:1682–1690PubMedCrossRef

17.

Mir O, Boudou-Rouquette P, Larousserie F, Blanchet B, Babinet A, Anract P, Goldwasser F (2012) Durable clinical activity of single-agent bevacizumab in a nonagenarian patient with metastatic alveolar soft part sarcoma. Anticancer Drugs 23:745–748PubMedCrossRef

18.

Azizi AA, Haberler C, Czech T, Gupper A, Prayer D, Breitschopf H, Acker T, Slavc I (2006) Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma. Lancet Oncol 7:521–523PubMedCrossRef

19.

Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, Turkbey IB, Lawrence S, Kinders RJ, Choyke P, Simon R, Steinberg SM, Doroshow JH, Helman L (2013) Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 31:2296–2302PubMedCentralPubMedCrossRef

20.

Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809PubMedCrossRef

21.

Ellis LM, Reardon DA (2010) Is there really a yin and yang to VEGF-targeted therapies? Lancet Oncol 11:809–811PubMedCrossRef

22.

Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73:539–549PubMedCrossRef

23.

Huang Y, Goel S, Duda DG, Fukumura D, Jain RK (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73:2943–2948PubMedCentralPubMedCrossRef

24.

Linehan WM, Srinivasan R, Garcia JA (2013) Non-clear cell renal cancer: disease-based management and opportunities for targeted therapeutic approaches. Semin Oncol 40:511–520PubMedCentralPubMedCrossRef

25.

Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, Medioni J, Peyrard S, Roncelin S, Verkarre V, Mejean A, Fridman WH, Oudard S, Tartour E (2010) A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33:991–998PubMedCrossRef

26.

Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R (2008) Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 14:6674–6682PubMedCrossRef

27.

Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157PubMedCrossRef

28.

Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H (2009) Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 69:2506–2513PubMedCentralPubMedCrossRef

29.

van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, Giaccone G, Haanen JB, van den Eertwegh AJ, Boven E, Hoekman K, de Gruijl TD (2008) Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin Cancer Res 14:5884–5892PubMedCrossRef

30.

Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–1310PubMedCrossRef

31.

Schatton T, Scolyer RA, Thompson JF, Mihm MC Jr (2014) Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Methods Mol Biol 1102:287–324PubMedCrossRef

32.

Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Venn A, Kanetsky PA, Groben PA, Hao H, Orlow I, Reiner AS, Luo L, Paine S, Ollila DW, Wilcox H, Begg CB, Berwick M (2013) Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol 31:4252–4259PubMedCentralPubMedCrossRef

33.

Parmiani G, Castelli C, Santinami M, Rivoltini L (2007) Melanoma immunology: past, present and future. Curr Opin Oncol 19:121–127PubMedCrossRef

34.

Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, Tanaka M, Park JH, Kamijuku H, Tsujikawa T, Kawamura N (2013) Cancer-induced immunosuppressive cascades and their reversal by molecular-targeted therapy. Ann N Y Acad Sci 1284:80–86PubMedCrossRef

35.

Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203:1651–1656PubMedCentralPubMedCrossRef

36.

Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, Peng W, Sullivan RJ, Lawrence DP, Hodi FS, Overwijk WW, Lizee G, Murphy GF, Hwu P, Flaherty KT, Fisher DE, Wargo JA (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 19:1225–1231PubMedCentralPubMedCrossRef

37.

Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, Zhang M, Cooper ZA, Frederick DT, Li Y, Zhang M, Joseph RW, Bernatchez C, Ekmekcioglu S, Grimm E, Radvanyi LG, Davis RE, Davies MA, Wargo JA, Hwu P, Lizee G (2012) Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 18:5329–5340PubMedCentralPubMedCrossRef

38.

Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedCrossRef

39.

Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA (2012) Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 18:1386–1394PubMedCrossRef

40.

Cooper ZA, Frederick DT, Juneja VR, Sullivan RJ, Lawrence DP, Piris A, Sharpe AH, Fisher DE, Flaherty KT, Wargo JA (2013) BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology 2:e26615PubMedCentralPubMedCrossRef

41.

Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553PubMedCrossRef

42.

Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Gorgens A, Giebel B, Schadendorf D, Paschen A (2013) Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer 133:1653–1663PubMedCrossRef

43.

Wilmott JS, Haydu LE, Menzies AM, Lum T, Hyman J, Thompson JF, Hersey P, Kefford RF, Scolyer RA, Long GV (2014) Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. J Immunol 192:2505–2513PubMedCrossRef

44.

Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, Haynes NM, Kinross K, Yagita H, Koya RC, Graeber TG, Ribas A, McArthur GA, Smyth MJ (2013) Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 123:1371–1381PubMedCentralPubMedCrossRef

45.

Allavena P, Mantovani A (2012) Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 167:195–205PubMedCentralPubMedCrossRef

46.

DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54–67PubMedCentralPubMedCrossRef

47.

De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23:277–286PubMedCrossRef

48.

Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795PubMedCentralPubMedCrossRef

49.

Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73:1128–1141PubMedCentralPubMedCrossRef

50.

Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272PubMedCrossRef

51.

Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D’Incalci M, Allavena P (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23:249–262PubMedCrossRef

52.

Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, Sanfilippo R, Casieri P, Collini P, Dileo P, Spreafico C, Stacchiotti S, Tamborini E, Tercero JC, Jimeno J, D’Incalci M, Gronchi A, Fletcher JA, Pilotti S, Casali PG (2007) Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8:595–602PubMedCrossRef

53.

Le Cesne A, Cresta S, Maki RG, Blay JY, Verweij J, Poveda A, Casali PG, Balana C, Schoffski P, Grosso F, Lardelli P, Nieto A, Alfaro V, Demetri GD (2012) A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 48:3036–3044PubMedCrossRef

Title: Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies
Authors: Chiara Castelli
Licia Rivoltini
Monica Rodolfo
Marcella Tazzari
Cristina Belgiovine
Paola Allavena
Publication date: 01-01-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 1/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1576-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

Cancer stem cells: perspectives for therapeutic targeting

Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy

Identification of tumor-binding scFv derived from clonally related B cells in tumor and lymph node of a patient with breast cancer

Cytokine production in peripheral blood cells of patients with differentiated thyroid cancer: elevated Th2/Th9 cytokine production before and reduced Th2 cytokine production after radioactive iodine therapy

Overcoming the toxicity hurdles of genetically targeted T cells

Evaluation of complement proteins as screening markers for colorectal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer