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

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

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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.

Original languageEnglish (US)
Pages (from-to)1111-1124
Number of pages14
JournalJournal of Clinical Investigation
Volume120
Issue number4
DOIs
StatePublished - Apr 1 2010

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Immunotherapy
Drug Therapy
Neoplasms
Cancer Vaccines
IGF Type 2 Receptor
Antigens
Perforin
Adoptive Transfer
Permeability
Up-Regulation
Apoptosis
T-Lymphocytes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ramakrishnan, R., Assudani, D., Nagaraj, S., Hunter, T., Cho, H. I., Antonia, S., ... Gabrilovich, D. I. (2010). Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. Journal of Clinical Investigation, 120(4), 1111-1124. https://doi.org/10.1172/JCI40269

Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. / Ramakrishnan, Rupal; Assudani, Deepak; Nagaraj, Srinivas; Hunter, Terri; Cho, Hyun Il; Antonia, Scott; Altiok, Soner; Celis, Esteban; Gabrilovich, Dmitry I.

In: Journal of Clinical Investigation, Vol. 120, No. 4, 01.04.2010, p. 1111-1124.

Research output: Contribution to journalArticle

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', Journal of Clinical Investigation, vol. 120, no. 4, pp. 1111-1124. https://doi.org/10.1172/JCI40269
Ramakrishnan, Rupal ; Assudani, Deepak ; Nagaraj, Srinivas ; Hunter, Terri ; Cho, Hyun Il ; Antonia, Scott ; Altiok, Soner ; Celis, Esteban ; Gabrilovich, Dmitry I. / Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 4. pp. 1111-1124.
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