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Requirement of Innate Immunity in Tumor-Bearing Mice Cured by Adoptive Immunotherapy Using Tumor-Draining Lymph Nodes
John Ammori1, Khaled Hamzeh1, Hallie Graor1
1Division of Surgical Oncology, Department of Surgery, University Hospitals Case Medical Center and Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
Background:
The purpose of this study was to determine the cellular effectors of both the adoptively transferred cells and the tumor-bearing host that participate in the antitumor response to adoptive immunotherapy using culture-activated tumor-draining lymph nodes (TDLNs).
Methods:
TDLNs harvested from mice with 4T1 carcinoma cells were fractionated to derive the L-selectin(low) subpopulation and activated ex vivo prior to in vitro cytokine release assays and adoptive transfer into BALB/c mice bearing 3-day established subcutaneous tumors. Tumor-bearing recipients were SCID (lacking T, B, and NK cells), Rag2 deficient (lacking T and B cells), and wild-type BALB/c mice.
Results:
Culture-activated L-selectin(low) 4T1 TDLN from BALB/c mice secreted significant levels of interferon-gamma in response to 4T1 but not control tumor cells in vitro. CD4 cells within the adoptively transferred effector cell population contributed significantly to the antitumor effect in vivo. Culture-activated L-selectin(low) TDLNs from BALB/c wild-type mice were able to cure Rag2 deficient but not SCID mice bearing 4T1 subcutaneous tumors, suggesting a requirement of NK cells within the innate immune system of the tumor-bearing host during the antitumor response.
Conclusions:
These results identify the cellular effectors involved in tumor regression following adoptive transfer and demonstrate the requirement for intact innate immunity within the tumor-bearing host.
Insights
Adoptive immunotherapy using activated tumor-draining lymph nodes (TDLNs) relies on CD4 cells and innate immunity. This study identified key cellular effectors for successful tumor regression in mice.
Area of Science:
- Immunology
- Cancer Research
- Cellular Biology
Background:
- Adoptive immunotherapy is a promising cancer treatment.
- Understanding the cellular mechanisms driving antitumor responses is crucial.
- Culture-activated tumor-draining lymph nodes (TDLNs) are a source of effector cells.
Purpose of the Study:
- To identify cellular effectors in adoptive immunotherapy using culture-activated TDLNs.
- To investigate the roles of transferred cells and the tumor-bearing host's immune system.
- To elucidate the mechanisms of antitumor response in a 4T1 carcinoma model.
Main Methods:
- Harvested TDLNs from 4T1 carcinoma-bearing mice were fractionated for L-selectin(low) subpopulations.
- Cells were activated ex vivo and subjected to cytokine release assays.
- Adoptive transfer was performed into SCID, Rag2 deficient, and wild-type BALB/c mice with subcutaneous tumors.
Main Results:
- Activated L-selectin(low) TDLNs secreted interferon-gamma in response to 4T1 tumor cells.
- CD4 cells within the transferred population significantly contributed to antitumor effects.
- Tumor cure was observed in Rag2 deficient but not SCID mice, indicating a role for NK cells.
Conclusions:
- Cellular effectors, including CD4 cells and NK cells, are critical for adoptive immunotherapy success.
- Intact innate immunity in the tumor-bearing host is essential for effective tumor regression.
- This study clarifies the cellular basis of antitumor responses in TDLN-based adoptive transfer.
