Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity

Arthur Machlenkin, Ofir Goldberger, Boaz Tirosh, Adrian Paz, Ilan Volovitz, Erez Bar-Haim, Sung Hyung Lee, Ezra Vadai, Esther Tzehoval, Lea Eisenbach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Purpose: Cryotherapy of localized prostate, renal and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low conplication rate in comparison with conventional surgery. The main drawback of cryotherapy is that it has no systemic effect on distant metastases. We investigated whether intratumoral injections of dendritic cells following cryotherapy of local tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local tumor destruction and systemic anticancer immunity. Experimental Designs: The 3LL murine Lewis lung carcinoma clone D122 and the ovalbumin-transfected B16 melanoma clone MO5 served as models for spontaneous metastasis. The antimetastatic effect of cryoimmunotherapy was assessed in the lung carcinoma model by monitoring mouse survival, lung weight, and induction of tumor-specific CTLs. The mechanism of cryoimmunotherapy was elucidated in the melanoma model using adoptive transfer of T cell receptor transgenic OT-1 CTLs into the tumor-bearing mice, and analysis of Th1/Th2 responses by intracellular cytokine staining in CD4 and CD8 cells. Results: Cryoimmunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival and dramatically reduced lung metastasis. Although intratumor administration of dendritic cells alone increased the proliferation rate of CD8 cells, only cryoimmunotherapy resulted in the generation of effector memory cells. Furthermore, cryoimmunotherapy protected mice that had survived primary MO5 tumors from rechallenge with parental tumors. Conclusions: These results present cryoimmunotherapy as a novel approach for systemic treatment of cancer. We envisage that cryotherapy of tumors combined with subsequent in situ immunotherapy by autologous unmodified immature dendritic cells can be applied in practice.

Original languageAmerican English
Pages (from-to)4955-4961
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number13
DOIs
StatePublished - 1 Jul 2005
Externally publishedYes

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