Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice
Top Cited Papers
Open Access
- 1 April 2010
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 120 (4) , 1111-1124
- https://doi.org/10.1172/jci40269
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.Keywords
This publication has 42 references indexed in Scilit:
- Full-length dominant-negative survivin for cancer immunotherapy.2003
- A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell deathThe Journal of cell biology, 2003
- Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer.2003
- An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53Gene Therapy, 2002
- Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradationCell Death & Differentiation, 2001
- Characterization of CD8 + cytotoxic T lymphocyte/tumor cell interactions reflecting recognition of an endogenously expressed murine wild-type p53 determinantCancer Immunology, Immunotherapy, 2001
- Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and BaxThe Journal of Experimental Medicine, 2000
- Initiation of Apoptosis by Granzyme B Requires Direct Cleavage of Bid, but Not Direct Granzyme B–Mediated Caspase ActivationThe Journal of Experimental Medicine, 2000
- Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is a Death Receptor for Granzyme B during Cytotoxic T Cell–Induced ApoptosisCell, 2000
- Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function.1999