Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma.
In contrast to chronic/long-term stress that suppresses/dysregulates immune function, an acute/short-term fight-or-flight stress response experienced during immune activation can enhance innate and adaptive immunity. Moderate ultraviolet-B (UV) exposure provides a non-invasive system for studying the naturalistic emergence, progression and regression of squamous cell carcinoma (SCC). Because SCC is an immunoresponsive cancer, we hypothesized that short-term stress experienced before UV exposure would enhance protective immunity and increase resistance to SCC. Control and short-term stress groups were treated identically except that the short-term stress group was restrained (2.5h) before each of nine UV-exposure sessions (minimum erythemal dose, 3-times/week) during weeks 4-6 of the 10-week UV exposure protocol. Tumors were measured weekly, and tissue collected at weeks 7, 20, and 32. Chemokine and cytokine gene expression was quantified by real-time PCR, and CD4+ and CD8+ T cells by flow cytometry and immunohistochemistry. Compared to controls, the short-term stress group showed greater cutaneous T-cell attracting chemokine (CTACK)/CCL27, RANTES, IL-12, and IFN-gamma gene expression at weeks 7, 20, and 32, higher skin infiltrating T cell numbers (weeks 7 and 20), lower tumor incidence (weeks 11-20) and fewer tumors (weeks 11-26). These results suggest that activation of short-term stress physiology increased chemokine expression and T cell trafficking and/or function during/following UV exposure, and enhanced Type 1 cytokine-driven cell-mediated immunity that is crucial for resistance to SCC. Therefore, the physiological fight-or-flight stress response and its adjuvant-like immuno-enhancing effects, may provide a novel and important mechanism for enhancing immune system mediated tumor-detection/elimination that merits further investigation.
Dhabhar
Firdaus S
FS
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5135, United States. dhabhar@gmail.com
Saul
Alison N
AN
Daugherty
Christine
C
Holmes
Tyson H
TH
Bouley
Donna M
DM
Oberyszyn
Tatiana M
TM
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D002452:Cell Count; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D007111:Immunity, Cellular / Q000276:immunology*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D013315:Stress, Psychological / Q000276:immunology* / Q000523:psychology; D013534:Survival; D014466:Ultraviolet Rays
D018925:Chemokines; D016207:Cytokines