Skip to main content

Advertisement

SpringerLink
Log in

Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer

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

Abstract

There is mounting evidence to support the use of a combination of immunotherapy with chemotherapy in the treatment of various types of cancers. However, the mechanism(s), by which these modalities are synergized, are not fully understood. In this review, we discuss several possible mechanisms of the combined effect of immunotherapy and chemotherapy of cancer. We will examine various aspects of this issue such as the combination of different treatment options, the dosage for each arm of treatment, and, more importantly, the timing and sequence of the administration of these treatments.

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.

Similar content being viewed by others

References

  1. Schlom J (2012) Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst 104:599–613. doi:10.1093/jnci/djs033

    Article  PubMed  CAS  Google Scholar 

  2. Green DR, Ferguson T, Zitvogel L, Kroemer G (2009) Immunogenic and tolerogenic cell death. Nat Rev Immunol 9:353–363

    Article  PubMed  CAS  Google Scholar 

  3. van der Most RG, Currie AJ, Robinson BW, Lake RA (2008) Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all. Cell Death Differ 15:13–20. doi:10.1038/sj.cdd.4402255

    Article  PubMed  Google Scholar 

  4. Yu B, Kusmartsev S, Cheng F, Paolini M, Nefedova Y, Sotomayor E, Gabrilovich D (2003) Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res 9:285–294

    PubMed  CAS  Google Scholar 

  5. Weiner HL, Cohen JA (2002) Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 8:142–154

    Article  PubMed  CAS  Google Scholar 

  6. Javeed A, Ashraf M, Riaz A, Ghafoor A, Afzal S, Mukhtar MM (2009) Paclitaxel and immune system. Eur J Pharm Sci 38:283–290. doi:10.1016/j.ejps.2009.08.009

    Article  PubMed  CAS  Google Scholar 

  7. Kaneno R, Shurin GV, Tourkova IL, Shurin MR (2009) Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J Transl Med 7:58. doi:10.1186/1479-5876-7-58

    Article  PubMed  Google Scholar 

  8. Nakahara T, Uchi H, Lesokhin AM et al (2010) Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. Blood 115:4384–4392. doi:10.1182/blood-2009-11-251231

    Article  PubMed  CAS  Google Scholar 

  9. Shurin GV, Tourkova IL, Kaneno R, Shurin MR (2009) Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol 183:137–144. doi:10.4049/jimmunol.0900734

    Article  PubMed  CAS  Google Scholar 

  10. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M (2000) Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 275:2251–2254

    Article  PubMed  CAS  Google Scholar 

  11. Perez-Diez A, Joncker NT, Choi K, Chan WF, Anderson CC, Lantz O, Matzinger P (2007) CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 109:5346–5354. doi:10.1182/blood-2006-10-051318

    Article  PubMed  CAS  Google Scholar 

  12. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 188:2357–2368

    Article  PubMed  CAS  Google Scholar 

  13. Ding ZC, Blazar BR, Mellor AL, Munn DH, Zhou G (2010) Chemotherapy rescues tumor-driven aberrant CD4 + T-cell differentiation and restores an activated polyfunctional helper phenotype. Blood 115:2397–2406. doi:10.1182/blood-2009-11-253336

    Article  PubMed  CAS  Google Scholar 

  14. Emens LA, Jaffee EM (2005) Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65:8059–8064

    Article  PubMed  CAS  Google Scholar 

  15. Amigorena S, Savina A (2010) Intracellular mechanisms of antigen cross presentation in dendritic cells. Curr Opin Immunol 22:109–117. doi:10.1016/j.coi.2010.01.022

    Article  PubMed  CAS  Google Scholar 

  16. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV (2007) Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 109:4839–4845. doi:10.1182/blood-2006-10-054221

    Article  PubMed  CAS  Google Scholar 

  17. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271. doi:10.1146/annurev-immunol-031210-101324

    Article  PubMed  CAS  Google Scholar 

  18. Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT (2007) Masquerader: high mobility group box-1 and cancer. Clin Cancer Res 13:2836–2848. doi:10.1158/1078-0432.CCR-06-1953

    Article  PubMed  CAS  Google Scholar 

  19. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689–3697

    PubMed  CAS  Google Scholar 

  20. Nigam A, Yacavone RF, Zahurak ML, Johns CM, Pardoll DM, Piantadosi S, Levitsky HI, Nelson WG (1998) Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. Int J Oncol 12:161–170

    PubMed  CAS  Google Scholar 

  21. Obeid M, Tesniere A, Ghiringhelli F et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54–61

    Article  PubMed  CAS  Google Scholar 

  22. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8:59–73

    Article  PubMed  CAS  Google Scholar 

  23. Liu WM, Fowler DW, Smith P, Dalgleish AG (2010) Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 102:115–123. doi:10.1038/sj.bjc.6605465

    Article  PubMed  CAS  Google Scholar 

  24. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  PubMed  CAS  Google Scholar 

  25. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  PubMed  CAS  Google Scholar 

  26. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 9:900–909

    Article  PubMed  CAS  Google Scholar 

  27. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1 +/CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11:6713–6721

    Article  PubMed  CAS  Google Scholar 

  28. Tseng CW, Hung CF, Alvarez RD et al (2008) Pretreatment with cisplatin enhances E7-specific CD8 + T-Cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res 14:3185–3192. doi:10.1158/1078-0432.CCR-08-0037

    Article  PubMed  CAS  Google Scholar 

  29. Zhang L, Dermawan K, Jin M et al (2008) Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219–229

    Article  PubMed  CAS  Google Scholar 

  30. Beyer M, Kochanek M, Darabi K et al (2005) Reduced frequencies and suppressive function of CD4 + CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106:2018–2025. doi:10.1182/blood-2005-02-0642

    Article  PubMed  CAS  Google Scholar 

  31. Vincent J, Mignot G, Chalmin F et al (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061. doi:10.1158/0008-5472.CAN-09-3690

    Article  PubMed  CAS  Google Scholar 

  32. Ugel S, Peranzoni E, Desantis G et al (2012) Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep 2:628–639. doi:10.1016/j.celrep.2012.08.006

    Article  PubMed  CAS  Google Scholar 

  33. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15–R24. doi:10.1172/JCI8829

    Article  PubMed  CAS  Google Scholar 

  34. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    PubMed  CAS  Google Scholar 

  35. Jurado JM, Sanchez A, Pajares B, Perez E, Alonso L, Alba E (2008) Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer. Clin Transl Oncol 10:583–586

    Article  PubMed  Google Scholar 

  36. Fontana A, Galli L, Fioravanti A et al (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15:4954–4962. doi:10.1158/1078-0432.CCR-08-3317

    Article  PubMed  CAS  Google Scholar 

  37. Bhatt RS, Merchan J, Parker R et al (2010) A phase 2 pilot trial of low-dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer 116:1751–1756. doi:10.1002/cncr.24902

    Article  PubMed  CAS  Google Scholar 

  38. Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047. doi:10.1172/JCI9872

    Article  PubMed  CAS  Google Scholar 

  39. Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465. doi:10.1038/nrclinonc.2010.82

    Article  PubMed  Google Scholar 

  40. Ghiringhelli F, Menard C, Puig PE et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4 + CD25 + regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648. doi:10.1007/s00262-006-0225-8

    Article  PubMed  CAS  Google Scholar 

  41. Banissi C, Ghiringhelli F, Chen L, Carpentier AF (2009) Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58:1627–1634. doi:10.1007/s00262-009-0671-1

    Article  PubMed  CAS  Google Scholar 

  42. Tanaka H, Matsushima H, Mizumoto N, Takashima A (2009) Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res 69:6978–6986. doi:10.1158/0008-5472.CAN-09-1101

    Article  PubMed  CAS  Google Scholar 

  43. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627. doi:10.1146/annurev.med.53.082901.103929

    Article  PubMed  CAS  Google Scholar 

  44. Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873. doi:10.1101/gad.1599207

    Article  PubMed  CAS  Google Scholar 

  45. Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6:439–448. doi:10.1038/nrm1660

    Article  PubMed  CAS  Google Scholar 

  46. Amaravadi RK, Thompson CB (2007) The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 13:7271–7279. doi:10.1158/1078-0432.CCR-07-1595

    Article  PubMed  CAS  Google Scholar 

  47. Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448–457. doi:10.1038/sj.cdd.4401359

    Article  PubMed  CAS  Google Scholar 

  48. Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I (2003) Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63:2103–2108

    PubMed  CAS  Google Scholar 

  49. Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann RS (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113(Pt 7):1189–1198

    PubMed  CAS  Google Scholar 

  50. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A (2009) DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 10:285–292. doi:10.1038/embor.2008.246

    Article  PubMed  CAS  Google Scholar 

  51. Djavaheri-Mergny M, Maiuri MC, Kroemer G (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29:1717–1719. doi:10.1038/onc.2009.519

    Article  PubMed  CAS  Google Scholar 

  52. Berardi DE, Campodonico PB, Diaz Bessone MI, Urtreger AJ, Todaro LB (2011) Autophagy: friend or foe in breast cancer development, progression, and treatment. Int J Breast Cancer 2011:595092. doi:10.4061/2011/595092

    PubMed  Google Scholar 

  53. Gong C, Bauvy C, Tonelli G et al. (2012) Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene. doi: 10.1038/onc.2012.252

  54. Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975. doi:10.1038/nrc2540

    Article  PubMed  CAS  Google Scholar 

  55. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353–361. doi:10.1016/j.molmed.2005.06.007

    Article  PubMed  CAS  Google Scholar 

  56. Wildenberg ME, Vos AC, Wolfkamp SC, Duijvestein M, Verhaar AP, Te Velde AA, van den Brink GR, Hommes DW (2012) Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse. Gastroenterology 142(1493–503):e6. doi:10.1053/j.gastro.2012.02.034

    PubMed  Google Scholar 

  57. Chemali M, Radtke K, Desjardins M, English L (2011) Alternative pathways for MHC class I presentation: a new function for autophagy. Cell Mol Life Sci 68:1533–1541. doi:10.1007/s00018-011-0660-3

    Article  PubMed  CAS  Google Scholar 

  58. Li C, Capan E, Zhao Y, Zhao J, Stolz D, Watkins SC, Jin S, Lu B (2006) Autophagy is induced in CD4 + T cells and important for the growth factor-withdrawal cell death. J Immunol 177:5163–5168

    PubMed  CAS  Google Scholar 

  59. Pua HH, Guo J, Komatsu M, He YW (2009) Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol 182:4046–4055. doi:10.4049/jimmunol.0801143

    Article  PubMed  CAS  Google Scholar 

  60. Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI (2010) Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 120:1111–1124

    Article  PubMed  CAS  Google Scholar 

  61. Stein M, Braulke T, Krentler C, Hasilik A, von Figura K (1987) 46-kDa mannose 6-phosphate-specific receptor: biosynthesis, processing, subcellular location and topology. Biol Chem Hoppe Seyler 368:937–947

    Article  PubMed  CAS  Google Scholar 

  62. Griffiths G, Hoflack B, Simons K, Mellman I, Kornfeld S (1988) The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 52:329–341

    Article  PubMed  CAS  Google Scholar 

  63. Dressel R, Raja SM, Honing S, Seidler T, Froelich CJ, von Figura K, Gunther E (2004) Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells. J Biol Chem 279:20200–20210

    Article  PubMed  CAS  Google Scholar 

  64. Trapani JA, Sutton VR, Thia KY, Li YQ, Froelich CJ, Jans DA, Sandrin MS, Browne KA (2003) A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J Cell Biol 160:223–233

    Article  PubMed  CAS  Google Scholar 

  65. Motyka B, Korbutt G, Pinkoski MJ et al (2000) Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103:491–500

    Article  PubMed  CAS  Google Scholar 

  66. Ramakrishnan R, Huang C, Cho HI et al. (2012) Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res. doi: 10.1158/0008-5472.CAN-12-2236

  67. Arlen PM, Gulley JL, Parker C et al (2006) A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 12:1260–1269

    Article  PubMed  CAS  Google Scholar 

  68. Garnett CT, Schlom J, Hodge JW (2008) Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res 14:3536–3544

    Article  PubMed  CAS  Google Scholar 

  69. Fridlender ZG, Sun J, Singhal S, Kapoor V, Cheng G, Suzuki E, Albelda SM (2010) Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther 18:1947–1959. doi:10.1038/mt.2010.159

    Article  PubMed  CAS  Google Scholar 

  70. Michaud M, Martins I, Sukkurwala AQ et al (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334:1573–1577

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

Authors declare no conflict of interests.

Author information

Authors and Affiliations

  1. H. Lee Moffitt Cancer Center and Research Institute, MRC 2067, 12902 Magnolia Dr., Tampa, FL, 33612, USA

    Rupal Ramakrishnan & Dmitry I. Gabrilovich

Authors
  1. Rupal Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dmitry I. Gabrilovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dmitry I. Gabrilovich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramakrishnan, R., Gabrilovich, D.I. Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer. Cancer Immunol Immunother 62, 405–410 (2013). https://doi.org/10.1007/s00262-012-1390-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1390-6

Keywords

Search

Navigation