[New strategy of cancer immunotherapy: irradiation or chemotherapeutics-induced lymphopenia combined with immune reconstitution and tumor vaccine].
OBJECTIVE
To test whether vaccination performed during irradiation or chemotherapeutics-induced lymphopenia-driven T cell proliferation could augment the antitumor immunity.


METHODS
The study composed of two parts, investigating the anti-tumor efficacy of performing tumor vaccination during early immune reconstitution period following sublethal total body irradiation and cyclophosphamide (Cy)-induced lymphopenia, respectively. Mice were subsequently reconstituted with naïve splenocytes from syngeneic mice and were named RLM (Reconstituted lymphopenic mice). Immunization/vaccination (F10) and adoptive immunotherapy (D5-G6) were used to explore anti-tumor immune responses in vaccinated irradiation/RLM and vaccinated Cy/RLM, respectively. Both normal C57BL/6 mice and RLM were vaccinated with irradiated, weakly immunogenic F10 melanoma cells and subsequently challenged with F10 cells. In addition, to determine the role of CD4(+) and CD8(+) T cells in the protective anti-tumor immune response, irradiation/RLM were depleted of these subpopulations by administration of the appropriate mAb around challenge. In the second part, adoptive immunotherapy was used to evaluate the anti-tumor immune responses under chemotherapeutics-induced lymphopenic condition. Both normal mice and RLM (Cy-treated) were vaccinated with GM-CSF-modified D5 melanoma cells (D5-G6) and tumor vaccine draining lymph nodes (TVDLN) were harvested 9-10 days later. Effector T cells were generated in vitro from TVDLN cells and adoptively transferred to mice bearing 3-day pre-established pulmonary metastases (D5). Recipient mice were sacrificed 2 weeks later after tumor inoculation and pulmonary metastases were enumerated.


RESULTS
Significantly greater protection was induced in vaccinated irradiation/RLM, compared to vaccinated normal mice (63.2% vs 16.7%). Protective immunity in RLM depended on CD8(+) T cells. Increase in the interval between reconstitution and vaccination significantly decrease the protection. Effector T cells generated from vaccinated Cy-treated RLM demonstrated significantly higher in vivo anti-tumor efficacy over those of vaccinated normal mice.


CONCLUSIONS
This study suggests that vaccination of RLM could elicit augmented antitumor immunity compared to normal hosts, highlighting the potential clinical benefit of performing tumor vaccination during irradiation or chemotherapeutics-induced lymphopenia in cancer patients.
Ma
Jun
J
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute for Cancer Research, Xi'an Jiaotong University, Xi'an 710061, China.
Wang
Yi-li
YL
Hu
Hong-ming
HM
Fox
Bernard A
BA
Si
Lü-sheng
LS
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000009:adverse effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D008231:Lymphopenia / Q000209:etiology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D014916:Whole-Body Irradiation
D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide