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Combination OX40 agonism/CTLA-4 blockade with vaccination reverses anergy and primes tumor-specific CD8 T cells in mice with spontaneous prostate cancer
© Linch et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Targeted immunotherapy, such as anti-CTLA-4 and anti-PD-1, has proven effective in treating cancer patients. However, despite these advances, cancer remains the second leading cause of death in the US. More effective strategies designed to maximize anti-tumor CD8 T cell responses are necessary to sustain long-term immunity. Agonist anti-OX40 and antagonist anti-CTLA-4 mAb augment the CD8 T cell response through different mechanisms. Therefore, we investigated the additive effects of these modalities on CD8 T cell responses. Combination anti-OX40/anti-CTLA-4 therapy more effectively primed antigen-specific CD8 T cells through enhanced expansion (82% of circulating CD8 T cells) compared to anti-OX40 (61%; P<0.05) or anti-CTLA-4 (41%; P<0.01) alone. Dual therapy also drove expansion of the polyclonal CD8 population. Moreover, combination therapy induced more proliferation (Ki-67) and differentiation (granzyme B, CD127, KLRG-1) following priming, suggesting potent additive effects of these modalities. However, it is known that tumors can induce T cell anergy, thereby limiting an effective anti-tumor response. We tested whether combination therapy could overcome anergy using a mouse model in which mice are tolerant to membrane-bound OVA. Combination anti-OX40/anti-CTLA-4 therapy was uniquely capable of driving robust expansion (12% of total CD8 in the spleen, vs. 2.5% anti-OX40, P<0.05, or 1% anti-CTLA-4, P<0.01) of anergic CD8 T cells, along with enhanced Ki-67 and granzyme B. To further drive expansion of antigen-specific CD8 T cells following therapy, we examined several methods of vaccination using nanoparticles, a Listeria monocytogenes vector, or anti-DEC-205 mAb (all conjugated to OVA) in the presence of anti-CD40. In anergic mice given combination therapy, vaccination with anti-DEC-205-OVA/anti-CD40 produced a 9-fold expansion of OT-I CD8 T cells compared to soluble OVA alone, greater than all other vectors combined. We next tested the efficacy of combination therapy with vaccination on anergy in a spontaneous model of prostate cancer. Combination therapy with vaccination drove expansion (2-fold over monotherapy, P<0.05) and differentiation (granzyme B, KLRG-1, CD25) of both anergic tumor-specific and polyclonal CD8 T cells. Importantly, dual therapy with vaccination enhanced the frequency and number of IFN-γ, TNF-α, and IL-2 producing CD8 T cells. These data indicate that anti-OX40/anti-CTLA-4 combination therapy with vaccination can uniquely augment and drive a robust CD8 T cell response capable of overcoming anergy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.