4T1 Mammary
Tumor Suppresses B- and T-cell Function In Vivo
Erika A. Danna, Beth A. Pulaski,
Mileka Gilbert, and Suzanne Ostrand-Rosenberg. Department of Biological
Sciences, UMBC, Baltimore, MD 21250.
We have generated novel tumor cell-based vaccines combining MHC class
II, CD80, Staphylococcal aureus enterotoxin B (SEB), and IL-12 to enhance
T-cell mediated immune responses against the highly metastatic 4T1 mouse
mammary carcinoma. This vaccine has been successful in reducing advanced
metastatic disease disseminating from primary 4T1 tumor that has been
established 2-4 weeks prior to initiation of immunotherapy. Mice left
untreated typically survive an average of 7 weeks post primary tumor challenge,
whereas 13% of the mice treated with the vaccine survive well past 27
weeks. The animals with the poorest prognosis (smallest increase in survival)
were those with a primary tumor >5 mm at the start of the immunotherapy.
Since others have shown that large primary tumor suppresses immune function,
we have hypothesized that 4T1 tumor induces immunosuppression in our system.
To test this hypothesis, we have measured in vivo responses to several
types of antigens, such as SEB superantigen, lipopolysaccharide (LPS),
B16F10 allogeneic tumor, and soluble Hen Egg Lysozyme (HEL), in naïve
versus tumor-bearing BALB/c mice. These experiments are unique because
they test immune function in vivo, thereby eliminating complications that
arise from technical problems in preparation procedures. We have chosen
SEB and LPS because they induce toxic shock syndrome in BALB/c mice through
T-cell and macrophage-dependent pathways, respectively. Growth of the
B16F10 tumor in BALB/c mice measures T-cell reactivity against allo-antigen,
while production of anti-HEL antibody measures B-cell reactivity against
foreign antigen. Our results demonstrate that antibody production, as
well as SEB-associated and allo-reactive T-cell function are either reduced
or suppressed in 2-4 week tumor-bearing animals. In contrast, macrophage
function is not altered. Experiments are underway to determine whether
apoptosis or anergy is being induced in immune cells. These findings will
offer insight into the immunocompetence of tumor-bearing individuals and
thereby lead to better strategies for designing tumor vaccines.
