Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice
Rupal Ramakrishnan, … , Esteban Celis, Dmitry I. Gabrilovich
Rupal Ramakrishnan, … , Esteban Celis, Dmitry I. Gabrilovich
Published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1111-1124. https://doi.org/10.1172/JCI40269.
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Research Article Oncology

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

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.

Authors

Rupal Ramakrishnan, Deepak Assudani, Srinivas Nagaraj, Terri Hunter, Hyun-Il Cho, Scott Antonia, Soner Altiok, Esteban Celis, Dmitry I. Gabrilovich

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Figure 7

Mechanism of synergistic antitumor activity of CTLs and chemotherapy.

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Mechanism of synergistic antitumor activity of CTLs and chemotherapy. (A...
(A) EL-4 cells loaded with control peptide and labeled with 51Cr were mixed at a 1:1 ratio with unlabeled EL-4 cells loaded with specific peptide. The mixture of target cells was incubated with OT-1 T cells at the indicated ratios. Pretreatment of target cells with TAX was performed overnight. Standard 4-hour chromium release assay was performed in duplicate. Experiments were repeated 3 times with the same results. Appropriate positive controls were set up with each experiment (data not shown). (B) The experiment was performed essentially as described in Figure 4A. As target cells, chromium-labeled 4T1 cells mixed with unlabeled 4T1-Neu cells were used. Effector T cells were obtained from splenocytes of BALB/c mice immunized with Neu-derived peptide as described in Methods. (C) Wild-type and B16F10Kb– tumor cells were used as targets in chromium release assay. Labeled target cells treated overnight with TAX were incubated in duplicate with T cells isolated from mice immunized with TRP-2–derived peptide as described in Methods. Two experiments with similar results were performed. (D) Unlabeled wild-type B16F10 tumor cells were mixed at 1:1 ratio with 51Cr labeled B16F10 cells with deleted H2Kb. These target cells were incubated with T cells from TRP-2–immunized mice, and cytotoxicity was evaluated in standard 4-hour 51Cr release assay. Two experiments with similar results were performed. Data are presented as mean ± SEM.