Recruitment of host CD8+ T cells by tumor-infiltrating lymphocytes and recombinant interleukin-2 during adoptive immunotherapy of cancer.
BACKGROUND
Previously we demonstrated that optimal doses of tumor-infiltrating lymphocytes (TIL) concomitant with recombinant interleukin-2 (rIL-2) effectively mediated complete tumor regression of murine 3-day pulmonary metastases.


METHODS
In the present study we have investigated the contribution of the host immune response to the effectiveness of adoptive immunotherapy with TIL in combination with low-dose rIL-2. All experiments were performed in a murine pulmonary metastases model induced by intravenous injection of methylcholanthrene-induced sarcoma (MCA-105) cells into C57BL/6 mice. As a novel approach we used monoclonal antibody specific for CD4+ or CD8+ T cells to deplete the host of its T-cell subpopulations.


RESULTS
Depletion of host CD8+ T cells 24 hours after tumor injection and 48 hours before TIL+rIL-2 treatment abrogated all antitumor activity of this type of immunotherapy and resulted in significant metastatic pulmonary disease (p < 0.001). In contrast, depletion of host CD4+ T cells did not alter the efficacy of TIL+rIL-2 treatment in tumor eradication. The loss of tumoricidal activity of TIL+rIL-2 treatment in a CD8+ T cell-depleted host could be overcome by adding back normal uneducated splenocytes 2 hours after TIL therapy (p < 0.001). In contrast, adding back CD8- CD4+ splenocytes to a CD8+ T cell-depleted host 2 hours after TIL+rIL-2 treatment resulted in significant pulmonary disease comparable to untreated animals.


CONCLUSIONS
We conclude that the recruitment of host CD8+ T cells by adoptively transferred TIL+rIL-2 appears to be important for effective tumor eradication in this type of immunotherapy.
Burger
U L
UL
Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chang
M P
MP
Goedegebuure
P S
PS
Eberlein
T J
TJ
Adams-Hodgins
S
S
D000818:Animals; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000628:therapy*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use
D007376:Interleukin-2; D011994:Recombinant Proteins