Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice.
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.
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Rupal
R
Ramakrishnan
Deepak
D
Assudani
Srinivas
S
Nagaraj
Terri
T
Hunter
Hyun-Il
HI
Cho
Scott
S
Antonia
Soner
S
Altiok
Esteban
E
Celis
Dmitry I
DI
Gabrilovich
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D053804:Granzymes / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D017239:Paclitaxel / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
D000970:Antineoplastic Agents; D053804:Granzymes; D017239:Paclitaxel; D002945:Cisplatin