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Published on: June 28, 2018
Murine lung cancer induces generalized T-cell exhaustion
Rohit Mittal1, Ching-Wen Chen1, John D Lyons1
1Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Background:
Cancer is known to modulate tumor-specific immune responses by establishing a microenvironment that leads to the upregulation of T-cell inhibitory receptors, resulting in the progressive loss of function and eventual death of tumor-specific T-cells. However, the ability of cancer to impact the functionality of the immune system on a systemic level is much less well characterized. Because cancer is known to predispose patients to infectious complications including sepsis, we hypothesized that the presence of cancer alters pathogen-directed immune responses on a systemic level.
Materials And Methods:
We assessed systemic T-cell coinhibitory receptor expression, cytokine production, and apoptosis in mice with established subcutaneous lung cancer tumors and in unmanipulated mice without cancer.
Results:
Results indicated that the frequencies of programmed death-1-positive, B and T lymphocyte attenuator-positive, and 2B4(+) cells in both the CD4(+) and CD8(+) T-cell compartments were increased in mice with localized cancer relative to non-cancer controls, and the frequencies of both CD4(+) and CD8(+) T-cells expressing multiple different inhibitory receptors were increased in cancer animals relative to non-cancer controls. Additionally, 2B4(+)CD8(+) T-cells in cancer mice exhibited reduced interleukin-2 and interferon-γ, whereas B and T lymphocyte attenuator-positive CD8(+) T-cells in cancer mice exhibited reduced interleukin-2 and tumor necrosis factor. Conversely, CD4(+) T-cells in cancer animals demonstrated an increase in the frequency of annexin V(+) apoptotic cells.
Conclusions:
Taken together, these data suggest that the presence of cancer induces systemic T-cell exhaustion and generalized immune suppression.
Insights
Cancer causes systemic immune suppression by increasing T-cell exhaustion and inhibitory receptor expression. This generalized immune suppression may explain why cancer patients are more susceptible to infections and sepsis.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Cancer modulates tumor-specific immunity by creating a microenvironment that upregulates T-cell inhibitory receptors.
- The systemic impact of cancer on immune system functionality is less understood.
- Cancer predisposes patients to infections and sepsis, suggesting systemic immune alterations.
Purpose of the Study:
- To investigate how cancer affects systemic immune responses.
- To test the hypothesis that cancer alters pathogen-directed immune responses systemically.
Main Methods:
- Assessed systemic T-cell coinhibitory receptor expression, cytokine production, and apoptosis.
- Utilized a mouse model with established subcutaneous lung cancer tumors.
- Compared cancer-bearing mice to unmanipulated control mice.
Main Results:
- Increased frequencies of programmed death-1, B and T lymphocyte attenuator, and 2B4-positive T-cells (CD4+ and CD8+) in cancer mice.
- Elevated expression of multiple inhibitory receptors on T-cells in cancer animals.
- Reduced interleukin-2 and interferon-γ in 2B4+CD8+ T-cells; reduced interleukin-2 and tumor necrosis factor in B and T lymphocyte attenuator+CD8+ T-cells.
- Increased frequency of apoptotic CD4+ T-cells (annexin V+) in cancer mice.
Conclusions:
- Cancer induces systemic T-cell exhaustion.
- Generalized immune suppression is a consequence of cancer presence.
- Findings suggest cancer broadly impairs immune function beyond the tumor site.
