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Natural killer cell lines kill autologous beta2-microglobulin-deficient melanoma cells: implications for cancer
A Porgador1, O Mandelboim, N P Restifo
1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Cancer vaccines used to generate specific cytotoxic T lymphocytes are not effective against tumor cells that have lost or suppressed expression of their class I major histocompatibility complex proteins. This loss is common in some cancers and particularly in metastatic lesions. We show that beta2-microglobulin-deficient class I-negative melanoma variants derived from patients undergoing specific T cell therapy are lysed by heterologous as well as autologous natural killer (NK) lines and clones, but not by specific T cells. Moreover, the minor NK cell fraction but not the major T cell fraction derived from heterologous lymphokine activated killer cells kills those tumor cell lines. ICAM-1 expression by the different class I protein deficient tumors was correlated with their sensitivity to lysis by NK cells. Adoptive autologous NK therapy may be an important supplement to consider in the design of new cancer immunotherapies.
Insights
Cancer cells lacking MHC class I proteins are resistant to T cell therapy. However, natural killer (NK) cells can effectively target these tumor cells, suggesting a role for NK cell therapy in cancer treatment.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Cancer vaccines targeting cytotoxic T lymphocytes (CTLs) are ineffective against tumor cells with suppressed or lost Class I Major Histocompatibility Complex (MHC) proteins.
- This MHC Class I downregulation is prevalent in various cancers, especially metastatic lesions, representing a significant challenge in cancer immunotherapy.
Purpose of the Study:
- To investigate the efficacy of natural killer (NK) cells against tumor cells deficient in MHC Class I expression.
- To explore the potential of adoptive NK cell therapy as a supplementary strategy for cancer immunotherapy.
Main Methods:
- Generation and analysis of beta2-microglobulin-deficient, Class I-negative melanoma variants from patients undergoing T cell therapy.
- Assessment of lysis sensitivity of these variants by both heterologous and autologous NK cell lines and clones.
- Evaluation of the cytotoxic activity of different immune cell fractions (NK vs. T cells) derived from lymphokine-activated killer (LAK) cells.
- Correlation of Intercellular Adhesion Molecule 1 (ICAM-1) expression with tumor cell lysis sensitivity.
Main Results:
- MHC Class I-deficient melanoma variants were susceptible to lysis by both autologous and heterologous NK cell lines and clones.
- Specific T cells did not effectively lyse these Class I-negative tumor cells.
- A minor NK cell fraction, but not the major T cell fraction, from heterologous LAK cells demonstrated killing activity against the target tumor cell lines.
- Tumor cell sensitivity to NK cell-mediated lysis was positively correlated with ICAM-1 expression.
Conclusions:
- NK cells represent a promising therapeutic avenue against tumors that evade T cell-mediated immunity due to MHC Class I loss.
- Adoptive autologous NK cell therapy could be a valuable addition to existing cancer immunotherapy strategies, particularly for treating cancers with MHC Class I deficiencies.