ASH: Regulation of Antigen Presenting Cell in Lymphoma Progression

[Guest guest]

[interesting]

Regulation of APC function during B Cell Lymphoma Progression

[80] Analysis of the Fate and Function of Antigen-Specific

CD8 T Cells

during B Cell Lymphoma Progression. Session Type: Oral

Session

Brayer, Fengdong Cheng, Pedro Horna, Ildefonso

Suarez, Hongwei Wang,

M. Sotomayor. Hematological Malignancies Program

and Immunology

Program, H. Lee Moffitt Cancer Center & Research Institute,

Tampa, FL, USA

There is now overwhelming evidence that tumor-induced

antigen (Ag)-specific

T cell tolerance represents a critical problem in tumor

immunology. [T

cells are a type of lymphocyte - immune cell - that acts

against foreign

antigens (proteins)]

Early studies of CD8 T cell tolerance equated peripheral

tolerance with

either ignorance or clonal deletion, although more recent

evidence has

suggested that this may be only partly accurate.

While murine [mouse] modeling outwardly supports the

contention that

high-affinity tumor-specific CD8 T cell responses are

centrally deleted,

cognate CD8 T cells displaying an Ag-experienced phenotype

[stage of

development/differentiation] can nonetheless be detected in

regional

draining lymph nodes (dLN) or in non-lymphoid sites where

the Ag is present.

However, these CD8 T cells are typically deficient in one

or more effector

functions, including cytokine [protein signal] production,

cytotoxicity

[ability to kill tumor], or proliferative [expand and grow]

capacity.

To better define the state of Ag-specific CD8 T cell

responsiveness in the

face of progressive tumor, we adoptively transferred

hemagglutinin (HA)

Ag-specific Clone 4 (CLN4) CD8 T cells into animals bearing

a genetically

modified B cell lymphoma expressing HA as a model tumor

antigen (A20HA).

Analysis of the fate and function of these transferred

antigen-specific CD8

T cells revealed that they encountered antigen in vivo [in

the body], were

capable of mounting an initial response to A20HA [a test

antigen] but this

response was not sustained [tolerance].

Indeed, while a prominent CTL [cytotoxic T- Lymphocytes]

activation was

observed in the spleen and draining lymph nodes of tumor

bearing mice within

14 days of T cell transfer, responses (HA-specific

proliferation, IFN-?

production and cytotoxicity) began to wane by day 21 after

T cell transfer,

and in particular their ability to produce IFN-?. [a

protein that indicates

activation of t-cells] A similar pattern of transient

activation followed by

loss of CD8 T cell function has been also observed in an in

vivo model of

high-dose peptide induced antigen-specific CD8 T cell

tolerance.

Given our recent demonstration that the disruption of Stat3

signaling in

APCs [antigen presenting cells - cells that present foreing

proteins to

t-cells] overcomes CD4 T cell tolerance we determined next

whether Stat3

deficient APCs may be inherently better at cross-presenting

tumor-Ags and

elicit therefore a more productive and sustained CD8 T cell

response.

In an in vitro system in which tumor cells expressing a

model tumor antigen

(EL4mOVA) were cultured with APCs genetically devoid of

Stat3 signaling and

anti-OVA CD8 T-cells (OT-I), we found that these T cells

displayed an

enhanced function relative to antigen-specific CD8 T-cells

that encountered

antigen on APCs with an intact Stat3 signaling.

Currently, we are investigating whether CD8 T-cell

tolerance to tumor

antigens occurred -or not- in tumor bearing mice with a

genetic disruption

of Stat3 signaling in APCs. Furthermore, given the emerging

role of other

members of the STAT family in regulation of APC function,

we are exploring

whether targeted disruption of Stat1, 4 and 6 can alter the

ability of the

CD8 T-cell to sustain a protective response or, more

importantly to recover

function once tolerance is induced.

Abstract #80 appears in Blood, Volume 104, issue 11,

November 16, 2004

Keywords: STAT3|Tolerance|Tumor immunity