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Tumour-induced suppression of immune response and its correction
G A Banat1, O Christ, B Cochlovius
1Department of Tumour Progression and Immune Defence, Germany Cancer Research Centre, Heidelberg.
Abstract:
Immunosuppressive features of tumour cells are a major obstacle for immunotherapy of cancer. We recently noted that RENCA cells effectively interfere with the in vivo activation of RENCA-specific T cells. To unravel the underlying mechanism, we evaluated the influence of RENCA cells on a mixed-lymphocyte/ tumour reaction as well as an allogeneic mixed-lymphocyte reaction. We observed that RENCA cells were not directly immunosuppressive. Instead, they initiated deviation of an immune response in at least two independent directions: (i) expansion of a population of NK1.1+/CD3+ cells, which was accompanied by elimination of mainly CD4+ lymphocytes, and (ii) production of a leukocyte-derived inhibitory factor. Expression of the costimulatory molecule B7.1 by RENCA cells prevented induction of anergy, while expression of MHC class II molecules prevented expansion of NK1.1+ cells, which was accompanied by a significant decrease in cell death. Hence, an unimpaired response was observed only when RENCA cells expressed B7.1 plus MHC class II molecules. Thus, even if a tumour itself is not immunosuppressive, it can induce a strong deviation of the immune response. It is concluded that the first contact between elements of the immune system and the tumour cell can confer a severe bias on immunoregulatory circuits.
Insights
Tumor cells can hinder cancer immunotherapy by disrupting T cell activation. This study reveals that RENCA cells redirect immune responses, impacting T cell populations and immune factor production.
Area of Science:
- Immunology
- Cancer Biology
- Immunotherapy
Background:
- Tumor cells possess immunosuppressive features, posing a significant challenge to effective cancer immunotherapy.
- RENCA cells were observed to interfere with the in vivo activation of RENCA-specific T cells, necessitating further investigation into the underlying mechanisms.
Purpose of the Study:
- To elucidate the mechanism by which RENCA cells interfere with T cell activation.
- To evaluate the influence of RENCA cells on mixed-lymphocyte/tumor reactions and allogeneic mixed-lymphocyte reactions.
Main Methods:
- Mixed-lymphocyte/tumor reaction assays
- Allogeneic mixed-lymphocyte reaction assays
- Flow cytometry to analyze cell populations (NK1.1+/CD3+, CD4+ lymphocytes)
- Assessment of leukocyte-derived inhibitory factor production
Main Results:
- RENCA cells were not directly immunosuppressive but induced immune response deviation.
- Immune deviation included expansion of NK1.1+/CD3+ cells, leading to CD4+ lymphocyte elimination, and production of a leukocyte-derived inhibitory factor.
- Expression of B7.1 by RENCA cells prevented anergy, while MHC class II expression inhibited NK1.1+ cell expansion and reduced cell death. An unimpaired response required both B7.1 and MHC class II expression.
Conclusions:
- Tumor cells can induce significant immune response deviation even without being directly immunosuppressive.
- The initial interaction between immune cells and tumor cells can profoundly bias immunoregulatory circuits.
- Understanding these tumor-induced immune deviations is crucial for developing effective cancer immunotherapies.