A retinoic acid--rich tumor microenvironment provides clonal survival cues for tumor-specific CD8(+) T cells.
While vitamin A has been implicated in host resistance to infectious disease, little is known about the role of vitamin A and its active metabolite, retinoic acid (RA) in host defenses against cancer. Here, we show that local RA production within the tumor microenvironment (TME) is increased up to 5-fold as compared with naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8(+) T cells using a dominant negative retinoic acid receptor α (dnRARα) established that RA signaling is required for tumor-specific CD8(+) T-cell expansion/accumulation and protective antitumor immunity. In vivo analysis of antigen-specific CD8(+) T-cell responses revealed that early T-cell expansion was RA-independent; however, late T-cell expansion and clonal accumulation was suppressed strongly in the absence of RA signaling. Our findings indicate that RA function is essential for the survival of tumor-reactive CD8(+) T cells within the TME.
Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03755, USA.
Yanxia
Y
Guo
Karina
K
Pino-Lagos
Cory A
CA
Ahonen
Kathy A
KA
Bennett
Jinshan
J
Wang
Joseph L
JL
Napoli
Rune
R
Blomhoff
Shanthini
S
Sockanathan
Roshantha A
RA
Chandraratna
Ethan
E
Dmitrovsky
Mary Jo
MJ
Turk
Randolph J
RJ
Noelle
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D059016:Tumor Microenvironment
D014212:Tretinoin