Specific Aims: Immune-based therapies offer a promising alternative treatment to radiotherapy- or chemotherapyresistant tumors, but enthusiasm is tempered by the fact that consistently successful treatment of patients has remained elusive. The reasons for this failure are likely multifaceted, and range from immunization strategies that generate relatively weak T cell responses, to the anti-inflammatory environment and associated mechanisms of immune suppression that tend to evolve within tumors. The broad, long-term objective of our research is to investigate immune modulators that can be used to enhance the magnitude and functional capacity of T cells that are targeted to tumors. One such modulator is CD70, a member of the TNFsuperfamily (TNFSF) of costimulatory molecules, whose receptor is CD27. We and others have recently demonstrated CD70 as being an important component of a dendritic cell (DC) that has been ?licensed? by activated CD4+ T cell (TCD4). As a prelude to examining the efficacy of CD70 for tumor immunotherapy, during the last funding period we have studied the mechanisms by which the expression of CD70 is induced upon DC, and the subsequent influence of CD70-mediated costimulation on TCD4 and CD8+ T cells (TCD8). Based on our observations that 1) CD70 is potently induced on DC in vivo by engaging both CD40 and TLR, 2) that blocking CD70-mediated costimulation reduces the survival and differentiation of effector TCD8 and 3) blocking CD70-mediated costimulation reduces the magnitude and IFN?-production of effector TCD4, we now hypothesize that interventions that cause the induction of CD70 expression, or the introduction of CD27- agonists (in the form of soluble CD70 or agonistic anti-CD27 antibodies) will result in enhanced control of tumor outgrowth by supporting the survival and functional activity of tumor-specific T cells. To test this hypothesis, we propose the following specific aims:
Specific Aim 1 : To determine whether CD70 is the critical immunogenic molecule expressed by DC activated by CD40-dependent and independent pathways. We will define the ability of TLR-ligands to synergize with CD40 agonists and/or TCD4 to induce the expression of CD70. We will determine the capacity of other immunostimulatory molecules to unilaterally induce CD70 expression, or cooperate with CD40-mediated stimulation. We will determine the relative immunogenicity of DC stimulated in these manners, and define the extent to which any enhancements to immunogenicity are dependent upon CD70 expression.
Specific Aim 2 : To determine whether CD27 agonists enhance TH1-differentiated TCD4 We will dissect the impact of CD70-mediated costimulation on the magnitude and differentiation status of primary and secondary TCD4 responses. We will determine the extent to which CD70-mediated costimulation can be utilized to enhance differentiation of TCD4 into IFN?-secreting effector cells.
Specific Aim 3 : To determine whether CD27 agonists enhance effector TCD8 responses. We will test the hypothesis that CD27 agonists can enhance primary TCD8 responses and lead to the generation of fully functional memory TCD8 in the presence or absence of TCD4. We will extend these studies to address whether CD27-agonists support recall TCD8 responses. We will determine the extent to which CD70-mediated costimulation contributes to the differentiation of effector or memory precursor TCD8.
Specific Aim 4 : To determine whether induction of CD70 or CD27-agonists can enhance immunological control of melanoma. We will assess the capacity of CD27 agonists to support therapeutic tumor control in two distinct manners. First, we will induce CD70 expression on endogenous DC by stimulation via CD40 and TLR. Second, we will utilize soluble CD70 or anti-CD27 to support either vaccine induced TCD4 and TCD8 or adoptively transferred T cell populations. From these studies we anticipate a thorough evaluation of the potential for CD27-agonists to be used for cancer therapy and also a greater understanding of the biology of CD70 expression and costimulation.
| Dong, Han; Franklin, Nathan A; Ritchea, Shane B et al. (2015) CD70 and IFN-1 selectively induce eomesodermin or T-bet and synergize to promote CD8+ T-cell responses. Eur J Immunol 45:3289-301 |
| Dong, Han; Franklin, Nathan A; Roberts, Drew J et al. (2012) CD27 stimulation promotes the frequency of IL-7 receptor-expressing memory precursors and prevents IL-12-mediated loss of CD8(+) T cell memory in the absence of CD4(+) T cell help. J Immunol 188:3829-38 |
| Roberts, Drew J; Franklin, Nathan A; Kingeter, Lara M et al. (2010) Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. J Immunother 33:769-79 |
| Van Deusen, Katherine E; Rajapakse, Rohan; Bullock, Timothy N J (2010) CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell-dependent, licensed CD8+ T cell responses. J Leukoc Biol 87:477-85 |
