Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non-Self-Tumor Antigens: Implications for Cancer Immunotherapy

TY - JOUR

T1 - Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non-Self-Tumor Antigens

T2 - Implications for Cancer Immunotherapy

AU - Pedersen, Sara R

AU - Sørensen, Maria R

AU - Buus, Søren

AU - Christensen, Jan P

AU - Thomsen, Allan Randrup

PY - 2013/10/1

Y1 - 2013/10/1

N2 - It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA-specific CD8 T cell response and compare it to that induced against non-self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA-specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non-self-Ag-specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA-specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.

AB - It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA-specific CD8 T cell response and compare it to that induced against non-self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA-specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non-self-Ag-specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA-specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.

U2 - 10.4049/jimmunol.1300555

DO - 10.4049/jimmunol.1300555

M3 - Journal article

C2 - 24018273

SN - 0022-1767

VL - 191

SP - 3955

EP - 3967

JO - Journal of immunology (Baltimore, Md. : 1950)

JF - Journal of immunology (Baltimore, Md. : 1950)

IS - 7

ER -