Abstract Book 2010 - CIMT Annual Meeting

111 Diekmann | Enhancing immunity & adjuvants
mTOR inhibition by Rapamycin after intranodal
RNA immunization improves the CD8+ memory
T-cell response qualitatively and quantitatively
Jan Diekmann 1 , Sebastian Attig 1 , Sebastian Kreiter 1 , Raouf Selmi 1 , Mustafa Diken 1 , Özlem
Türeci 1 and Ugur Sahin 1,2
1 Universitätsmedizin, Johannes Gutenberg-Universität Mainz, Germany
2 Institute for Translational Oncoclogy (TrOn), Johannes Gutenberg-Universität Mainz, Germany
Memory T cell formation is one of the most im-
portant factors predicting the success of a cancer
vaccine. By inducing a long lasting antigen-specific
T cell memory, residual cancer cells and micro-metastasises
can be targeted and thereby a possible
relapse of the tumour can be prevented. Recent
reports have suggested the key metabolic kinase
mammalian target of rapamycin (mTOR) as an intrinsic
regulator of memory formation in the CD8+
T cell compartment. The inhibitor of mTOR, Rapamycin,
is used in the clinic to suppress immune rejection
in the setting of organ transplants. Paradoxically
it has been shown that Rapamycin treatment
of mice during and after the course of an infection
enhanced the formation and differentiation of the
memory CD8+ T cell pool and also accelerated the
transition from effector to memory cells.
In order to investigate the effect of Rapamycin on
the CD8+ T cell reponse in the setting of intranodal
RNA immunization, we treated C57BL/6J mice
with Rapamycin (Rapamune) for 3 weeks (d10 –
d31) after a course of three RNA immunizations
(d0, d3, d6) with IVT-RNA (20µg) coding for the
OVA-derived SIINFEKL epitope (SIINFEKL-RNA).
Immunized mice treated with the carrier of the drug
served as a control group. During the treatment, the
contraction of the SIINFEKL-specific CD8+ T cells
was almost identical in both groups. However, the
phenotype of the SIINFEKL-specific cells was markedly
different: the Rapamycin-group developed
significantly more CD127+/KLRG1- cells, potential
precursors of long-lived central memory cells. Additionally,
these cells showed a higher proliferative
capacity after a rechallenge with the antigen (SIIN-
FEKL peptide) at day +35. In this study, we show,
for the first time, the beneficiary effect of Rapamycin
on memory T cell differentiation in the setting
of anti-cancer vaccination.
These findings indicate that mTOR inhibitors could
be used to improve the establishment of a longlasting
and potent memory CD8+ T cell population
after intranodal RNA-immunization, which
could augment the outcome after tumour relapse/
therapy.
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