Skip to main content

Advertisement

SpringerLink
Log in

Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student’s t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D–NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fowler NH, McLaughlin P, Kwak L, Hagemeister F, Fanale M, Fayad L, Pro B, Samaniego F (2009) Lenalidomide and rituximab for untreated indolent non-Hodgkin’s lymphoma [abstract]. J Clin Oncol 27(15s):8548

    Google Scholar 

  2. Veliz M, Santana R, Lancet JE, Komrokji RS, Kharfan-Dabaja MA, Powers JJ, Dubovsky JA, Tinsley S, Deaver D, Sotomayor EM, Pinilla-Ibarz J (2009) Phase II study of lenalidomide in combination with rituximab for patients with CD5+/CD20+ hematologic malignancies who relapse or progress after rituximab. interim analysis [abstract]. Blood 114:2376

    Google Scholar 

  3. Ahmadi T, Chong EA, Gordon A, Aqui NA, Downs LH, Leinbach L, Goldstein SC, Nasta SD, Janofsky S, Maniar TN, Svoboda J, Schuster SJ (2009) Phase II trial of lenalidomide–dexamethasone–rituximab in relapsed or refractory indolent B-cell or mantle cell lymphomas resistant to rituximab [abstract]. Blood 114:1700

    Google Scholar 

  4. Kalmadi S, Davis M, Dowlati A, O’Keefe S, Cline-Burkhardt M, Pelley RJ, Borden E, Dreicer R, Bukowski R, Mekhail T (2007) Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors. Invest New Drugs 25:211–216. doi:10.1007/s10637-006-9025-4

    Article  CAS  PubMed  Google Scholar 

  5. Petrylak DP, Resto-Garces K, Tibyan M, Mohile SG (2009) A phase I open-label study using lenalidomide and docetaxel in castration- resistant prostate cancer [abstract]. J Clin Oncol 27(15s):5156

    Google Scholar 

  6. Sanborn SL, Gibbons J, Krishnamurthi S, Brell JM, Dowlati A, Bokar JA, Nock C, Horvath N, Bako J, Remick SC, Cooney MM (2009) Phase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors. Invest New Drugs 27:453–460. doi:10.1007/s10637-008-9200-x

    Article  CAS  PubMed  Google Scholar 

  7. Choueiri TK, Dreicer R, Rini BI, Elson P, Garcia JA, Thakkar SG, Baz RC, Mekhail TM, Jinks HA, Bukowski RM (2006) Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107:2609–2616. doi:10.1002/cncr.22290

    Article  CAS  PubMed  Google Scholar 

  8. Liu WM, Henry JY, Meyer B, Bartlett JB, Dalgleish AG, Galustian C (2009) Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs). Br J Cancer 101:803–812. doi:10.1038/sj.bjc.6605206

    Article  CAS  PubMed  Google Scholar 

  9. Lu L, Payvandi F, Wu L, Zhang LH, Hariri RJ, Man HW, Chen RS, Muller GW, Hughes CC, Stirling DI, Schafer PH, Bartlett JB (2009) The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 77:78–86. doi:10.1016/j.mvr.2008.08.003

    Article  CAS  PubMed  Google Scholar 

  10. Haslett PA, Hanekom WA, Muller G, Kaplan G (2003) Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 187:946–955. doi:10.1086/368126

    Article  CAS  PubMed  Google Scholar 

  11. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163:380–386

    CAS  PubMed  Google Scholar 

  12. Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG (2002) Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol 130:75–84. doi:10.1046/j.1365-2249.2002.01954.x

    Article  CAS  PubMed  Google Scholar 

  13. Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, Kumar S, Chauhan D, Treon SP, Richardson P, Anderson KC (2005) Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 128:192–203. doi:10.1111/j.1365-2141.2004.05286.x

    Article  CAS  PubMed  Google Scholar 

  14. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210–216

    Article  CAS  PubMed  Google Scholar 

  15. LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, Mitsiades C, Cheema P, Chauhan D, Richardson PG, Anderson KC, Munshi NC (2004) Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 103:1787–1790. doi:10.1182/blood-2003-02-0361

    Article  CAS  PubMed  Google Scholar 

  16. Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, Jagannath S, Dhodapkar MV (2006) Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 108:618–621. doi:10.1182/blood-2005-10-4184

    Article  CAS  PubMed  Google Scholar 

  17. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS (2005) Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 11:5984–5992. doi:10.1158/1078-0432.CCR-05-0577

    Article  CAS  PubMed  Google Scholar 

  18. Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB (2008) Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 14:4650–4657. doi:10.1158/1078-0432.CCR-07-4405

    Article  CAS  PubMed  Google Scholar 

  19. Lapalombella R, Gowda A, Joshi T, Mehter N, Cheney C, Lehman A, Chen CS, Johnson AJ, Caligiuri MA, Tridandapani S, Muthusamy N, Byrd JC (2009) The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia. Br J Haematol 144:848–855. doi:10.1111/j.1365-2141.2008.07548.x

    Article  CAS  PubMed  Google Scholar 

  20. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, Song W, Podar K, Hideshima T, Chauhan D, Schlossman R, Richardson P, Treon SP, Grewal IS, Munshi NC, Anderson KC (2005) Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 65:11712–11720. doi:10.1158/0008-5472.CAN-05-1657

    Article  CAS  PubMed  Google Scholar 

  21. Awan FT, Lapalombella R, Trotta R, Butchar JP, Yu B, Benson DM Jr, Roda JM, Cheney C, Mo X, Lehman A, Jones J, Flynn J, Jarjoura D, Desjarlais JR, Tridandapani S, Caligiuri MA, Muthusamy N, Byrd JC (2010) CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain engineered monoclonal antibody. Blood 115:1204–1213. doi:10.1182/blood-2009-06-229039

    Article  CAS  PubMed  Google Scholar 

  22. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, Czuczman MS (2008) Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol 140:36–45. doi:10.1111/j.1365-2141.2007.06841.x

    CAS  PubMed  Google Scholar 

  23. Zhu D, Corral LG, Fleming YW, Stein B (2008) Immunomodulatory drugs revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 57:1849–1859. doi:10.1007/s00262-008-0512-7

    Article  CAS  PubMed  Google Scholar 

  24. Xu Y, Wu H, Sun J, Seeger RC (2009) Activation of antitumor functions of natural killer cells and suppression of pro-tumor functions of monocytes by lenalidomide [abstract]. J Immunother 32:965

    Google Scholar 

  25. Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, Kristeleit H, Polychronis A, Pandha H, Muller GW, Stirling DI, Zeldis J, Dalgleish AG (2004) Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer 90:955–961. doi:10.1038/sj.bjc.6601579

    Article  CAS  PubMed  Google Scholar 

  26. Ayello J, Berg SL, Krailo M, van de Ven C, Ingle AM, Lewis D, Harrison L, Blaney S, Adamson PC, Cairo MS (2008) Lenalidomide (LMID) significantly enhances circulating serum levels of IL-2 and IL-15 levels, NK expansion and activation and NK and LAK cytotoxicity in children with refractory/recurrent solid tumors: a children’s oncology phase I consortium report [abstract]. Blood 112:107

    Google Scholar 

  27. Zamai L, Ponti C, Mirandola P, Gobbi G, Papa S, Galeotti L, Cocco L, Vitale M (2007) NK cells and cancer. J Immunol 178:4011–4016

    CAS  PubMed  Google Scholar 

  28. El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, Cook G, Feyler S, Richards SJ, Davies FE, Morgan GJ, Cook GP (2007) The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res 67:8444–8449. doi:10.1158/0008-5472.CAN-06-4230

    Article  CAS  PubMed  Google Scholar 

  29. Li K, Mandai M, Hamanishi J, Matsumura N, Suzuki A, Yagi H, Yamaguchi K, Baba T, Fujii S, Konishi I (2009) Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol Immunother 58:641–652. doi:10.1007/s00262-008-0585-3

    Article  CAS  PubMed  Google Scholar 

  30. Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–738. doi:10.1038/nature01112

    Article  CAS  PubMed  Google Scholar 

  31. Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J, Neuberg D, Anderson KC, Carrasco DR, Dranoff G (2008) MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA 105:1285–1290. doi:10.1073/pnas.0711293105

    Article  CAS  PubMed  Google Scholar 

  32. Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105:2066–2073. doi:10.1182/blood-2004-09-3548

    Article  CAS  PubMed  Google Scholar 

  33. Castriconi R, Dondero A, Corrias MV, Lanino E, Pende D, Moretta L, Bottino C, Moretta A (2004) Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction. Cancer Res 64:9180–9184. doi:10.1158/0008-5472.CAN-04-2682

    Article  CAS  PubMed  Google Scholar 

  34. Ravetch JV, Perussia B (1989) Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med 170:481–497

    Article  CAS  PubMed  Google Scholar 

  35. Diermayr S, Himmelreich H, Durovic B, Mathys-Schneeberger A, Siegler U, Langenkamp U, Hofsteenge J, Gratwohl A, Tichelli A, Paluszewska M, Wiktor-Jedrzejczak W, Kalberer CP, Wodnar-Filipowicz A (2008) NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 111:1428–1436. doi:10.1182/blood-2007-07-101311

    Article  CAS  PubMed  Google Scholar 

  36. Schneider-Merck T, Lammerts van Bueren JJ, Berger S, Rossen K, van Berkel PH, Derer S, Beyer T, Lohse S, Bleeker WK, Peipp M, Parren PW, van de Winkel JG, Valerius T, Dechant M (2010) Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol 184:512–520. doi:10.4049/jimmunol.0900847

    Article  CAS  PubMed  Google Scholar 

  37. López-Albaitero A, Lee SC, Morgan S, Grandis JR, Gooding WE, Ferrone S, Ferris RL (2009) Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 58:1853–1864. doi:10.1007/s00262-009-0697-4

    Article  PubMed  Google Scholar 

  38. Lapalombella R, Yu B, Triantafillou G, Liu Q, Butchar JP, Lozanski G, Ramanunni A, Smith LL, Blum W, Andritsos L, Wang DS, Lehman A, Chen CS, Johnson AJ, Marcucci G, Lee RJ, Lee LJ, Tridandapani S, Muthusamy N, Byrd JC (2008) Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells. Blood 112:5180–5189. doi:10.1182/blood-2008-01-133108

    Article  CAS  PubMed  Google Scholar 

  39. Hatjiharissi E, Xu L, Santos DD, Hunter ZR, Ciccarelli BT, Verselis S, Modica M, Cao Y, Manning RJ, Leleu X, Dimmock EA, Kortsaris A, Mitsiades C, Anderson KC, Fox EA, Treon SP (2007) Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood 110:2561–2564. doi:10.1182/blood-2007-01-070656

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by Celgene Corporation, Summit, NJ, USA. The authors received editorial support in the preparation of this manuscript, funded by Celgene. The authors were fully responsible for content and editorial decisions for this manuscript.

Conflict of interest

All of the authors are employees of Celgene Corporation.

Author information

Authors and Affiliations

  1. Celgene Corporation, 86 Morris Ave, Summit, NJ, 07901, USA

    Lei Wu, Anastasia Parton, Ling Lu, Mary Adams, Peter Schafer & J. Blake Bartlett

Authors
  1. Lei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anastasia Parton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Schafer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Blake Bartlett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Blake Bartlett.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 45 kb)

Supplementary material 2 (DOC 36 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., Parton, A., Lu, L. et al. Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers. Cancer Immunol Immunother 60, 61–73 (2011). https://doi.org/10.1007/s00262-010-0919-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0919-9

Keywords

Search

Navigation