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Differential tumor surveillance by natural killer (NK) and NKT cells
M J Smyth1, K Y Thia, S E Street
1Cellular Cytotoxicity Laboratory, Austin Research Institute, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia. m.smyth@ari.unimelb.edu.au
Abstract:
Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12 does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12. A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor Jalpha281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.
Insights
Host immune cells like natural killer (NK) and NK1.1(+) T (NKT) cells combat tumors. NKT cells protect against spontaneous tumors, particularly when interleukin-12 (IL-12) is not essential for the immune response.
Area of Science:
- Immunology
- Cancer Biology
- Innate Immunity
Background:
- The host's natural immune system plays a crucial role in tumor surveillance.
- Interleukin-12 (IL-12) is a cytokine that influences the innate immune response, but its role in tumor surveillance is not fully understood.
- Natural killer (NK) and NK1.1(+) T (NKT) cells are key components of the innate immune system with potential anti-tumor functions.
Purpose of the Study:
- To investigate the roles of endogenous interleukin-12 (IL-12) and specific immune cells in controlling tumor initiation and metastasis.
- To determine the relative importance of natural killer (NK) cells and NK1.1(+) T (NKT) cells in different tumor models.
- To elucidate the conditions under which NKT cells exert an anti-tumor function.
Main Methods:
- Utilized six distinct mouse tumor models.
- Employed gene-targeted mice and lymphocyte subset-depleted mice.
- Analyzed the impact of IL-12 dependency on tumor rejection and metastasis.
Main Results:
- CD3(-) NK cells were crucial for tumor rejection and metastasis prevention in IL-12-independent models.
- NKT cells demonstrated a protective role specifically in tumor models where IL-12 activity was required for rejection.
- T cell receptor Jalpha281 gene-targeted mice showed NKT cells are vital for protection against spontaneous methylcholanthrene-induced tumors.
Conclusions:
- NK cells are critical for tumor control when IL-12 is not a limiting factor.
- NKT cells possess an anti-tumor function, particularly in IL-12-dependent scenarios.
- This study is the first to describe an intrinsic anti-tumor role for NKT cells without external stimulation.