Murine lung cancer induces generalized T-cell exhaustion.
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.


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.
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Rohit
R
Mittal
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Ching-Wen
CW
Chen
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
John D
JD
Lyons
Department of Infectious Diseases and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Lindsay M
LM
Margoles
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Zhe
Z
Liang
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia.
Craig M
CM
Coopersmith
Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia. Electronic address: mandy.ford@emory.edu.
Mandy L
ML
Ford
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
C488868:BTLA protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic
Immune dysregulation; Immunology; Inflammation; T lymphocyte