Home LiteratureArticle Details
PMID: 20234093 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice.

The Journal of clinical investigation ·Vol. 120 ·No. 4 ·2010-04-00 ·Pages 1111-24

Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI

Abstract

Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Cell Line, Tumor Cisplatin/pharmacology Cytotoxicity, Immunologic/drug effects Dendritic Cells/immunology Female Granzymes/physiology Humans Immunotherapy Mice Mice, Inbred C57BL Neoplasms, Experimental/immunology,therapy Paclitaxel/pharmacology T-Lymphocytes, Cytotoxic/immunology Vaccination
Chemicals
Antineoplastic Agents Granzymes Paclitaxel Cisplatin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Ramakrishnan Rupal
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Assudani Deepak
Nagaraj Srinivas
Hunter Terri
Cho Hyun-Il
Antonia Scott
Altiok Soner
Celis Esteban
Gabrilovich Dmitry I
References (42)
42 references, click to expand
  1. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function.
    Clin Cancer Res. 1999 Oct;5(10):2963-70 PMID: 10537366
  2. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis.
    Cell. 2000 Oct 27;103(3):491-500 PMID: 11081635
  3. Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax.
    J Exp Med. 2000 Nov 20;192(10):1391-402 PMID: 11085742
  4. Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation.
    J Exp Med. 2000 Nov 20;192(10):1403-14 PMID: 11085743
  5. Characterization of CD8+ cytotoxic T lymphocyte/tumor cell interactions reflecting recognition of an endogenously expressed murine wild-type p53 determinant.
    Cancer Immunol Immunother. 2001 Jan;49(11):603-12 PMID: 11225991
  6. Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation.
    Cell Death Differ. 2001 Dec;8(12):1136-42 PMID: 11753562
  7. An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53.
    Gene Ther. 2002 Mar;9(5):345-52 PMID: 11938454
  8. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer.
    Clin Cancer Res. 2003 Jan;9(1):285-94 PMID: 12538481
  9. A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death.
    J Cell Biol. 2003 Jan 20;160(2):223-33 PMID: 12538642
  10. Full-length dominant-negative survivin for cancer immunotherapy.
    Clin Cancer Res. 2003 Dec 15;9(17):6523-33 PMID: 14695157
  11. Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells.
    J Biol Chem. 2004 May 7;279(19):20200-10 PMID: 14985351
  12. Cancer immunotherapy: moving beyond current vaccines.
    Nat Med. 2004 Sep;10(9):909-15 PMID: 15340416
  13. A mouse mutant p53 product recognized by CD4+ and CD8+ T cells.
    Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3171-5 PMID: 7909159
  14. IL-12 and mutant P53 peptide-pulsed dendritic cells for the specific immunotherapy of cancer.
    J Immunother Emphasis Tumor Immunol. 1996 Nov;19(6):414-8 PMID: 9041460
  15. Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice.
    J Exp Med. 1998 Aug 3;188(3):589-96 PMID: 9687535
  16. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations.
    Oncogene. 2005 Apr 21;24(18):3054-8 PMID: 15735684
  17. Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy.
    Clin Cancer Res. 2005 Jun 15;11(12):4430-6 PMID: 15958627
  18. Leveraging the activity of tumor vaccines with cytotoxic chemotherapy.
    Cancer Res. 2005 Sep 15;65(18):8059-64 PMID: 16166275
  19. Granule-mediated killing by granzyme B and perforin requires a mannose 6-phosphate receptor and is augmented by cell surface heparan sulfate.
    Mol Biol Cell. 2006 Feb;17(2):623-33 PMID: 16280358
  20. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer.
    Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):878-87 PMID: 16467102
  21. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.
    Clin Cancer Res. 2006 Feb 15;12(4):1260-9 PMID: 16489082
  22. Regulatory T cells, tumour immunity and immunotherapy.
    Nat Rev Immunol. 2006 Apr;6(4):295-307 PMID: 16557261
  23. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.
    Toxicol Sci. 2006 Nov;94(1):217-25 PMID: 16896059
  24. Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors.
    Cancer Res. 2007 Feb 1;67(3):1326-34 PMID: 17283170
  25. Immunosuppressive strategies that are mediated by tumor cells.
    Annu Rev Immunol. 2007;25:267-96 PMID: 17134371
  26. Apoptosis induced by the lymphocyte effector molecule perforin.
    Curr Opin Immunol. 2007 Jun;19(3):339-47 PMID: 17442557
  27. Cancer vaccines: moving beyond current paradigms.
    Clin Cancer Res. 2007 Jul 1;13(13):3776-82 PMID: 17606707
  28. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
    Nat Med. 2007 Sep;13(9):1050-9 PMID: 17704786
  29. Immunological aspects of cancer chemotherapy.
    Nat Rev Immunol. 2008 Jan;8(1):59-73 PMID: 18097448
  30. A chitosan hydrogel-based cancer drug delivery system exhibits synergistic antitumor effects by combining with a vaccinia viral vaccine.
    Int J Pharm. 2008 Feb 28;350(1-2):27-34 PMID: 17897800
  31. Inhibitory B7-family molecules in the tumour microenvironment.
    Nat Rev Immunol. 2008 Jun;8(6):467-77 PMID: 18500231
  32. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement.
    Clin Cancer Res. 2008 Jun 1;14(11):3536-44 PMID: 18519787
  33. Combined modality immunotherapy and chemotherapy: a new perspective.
    Cancer Immunol Immunother. 2008 Oct;57(10):1523-9 PMID: 18488219
  34. Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer.
    Clin Cancer Res. 2008 Aug 1;14(15):4843-9 PMID: 18676757
  35. Optimized DNA vaccines to specifically induce therapeutic CD8 T cell responses against autochthonous breast tumors.
    Cancer Immunol Immunother. 2008 Nov;57(11):1695-703 PMID: 18253731
  36. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy.
    Clin Immunol. 2008 Nov;129(2):219-29 PMID: 18771959
  37. Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients.
    Int J Cancer. 2009 Jan 1;124(1):130-9 PMID: 18839429
  38. Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse.
    Cancer Immunol Immunother. 2009 Apr;58(4):615-28 PMID: 18802696
  39. Use of tumour-responsive T cells as cancer treatment.
    Lancet. 2009 Feb 21;373(9664):673-83 PMID: 19231634
  40. Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts.
    Cancer Immunol Immunother. 2009 May;58(5):737-48 PMID: 18815785
  41. Myeloid-derived suppressor cells as regulators of the immune system.
    Nat Rev Immunol. 2009 Mar;9(3):162-74 PMID: 19197294
  42. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination.
    Clin Cancer Res. 2004 Aug 15;10(16):5316-26 PMID: 15328167
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI40269
Published
2010-04-00
Epub
2010-00-15
Pages
1111-24
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2846048
Subset
IM
Grants
NCI NIH HHS · K24 CA128953 · United States
NCI NIH HHS · R01 CA103921 · United States
NCI NIH HHS · R01CA103921 · United States
Corrections
CommentIn
PMID: 20527681
External Links
PubMed source DOI: 10.1172/JCI40269 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2