Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity.
OBJECTIVE
Cryotherapy of localized prostate, renal, and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low complication 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.


METHODS
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-I 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, cryoimmunotherapyprotected 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.
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Arthur
A
Machlenkin
Ofir
O
Goldberger
Boaz
B
Tirosh
Adrian
A
Paz
Ilan
I
Volovitz
Erez
E
Bar-Haim
Sung-Hyung
SH
Lee
Ezra
E
Vadai
Esther
E
Tzehoval
Lea
L
Eisenbach
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D017679:Cryotherapy / Q000379:methods*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D019041:L-Selectin / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000276:immunology / Q000517:prevention & control*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome
D018960:Hyaluronan Receptors; D011948:Receptors, Antigen, T-Cell; D019041:L-Selectin; D015847:Interleukin-4; D007371:Interferon-gamma