Project Summary
Adoptive cell transfer (ACT) therapies using tumor infiltrating T lymphocytes (TIL) for cancer patients have
failed to fulfill their full potential, mostly due to the transfer of exhausted, short-lived CD8+ T cells. Recently, we
discovered that T cell fitness can be improved by activating B cells in a TIL culture with the Toll-like receptor 9
(TLR) agonist CpG. Understanding and manipulating the TLR pathways that sustain T cell persistence will
potentially unlock durable responses to tumors. Further, there is little research on how B and CD8+ T cells interact
to promote T cell tumor immunity. In this proposal we seek to elucidate the mechanism by which T cells
generated from a CpG-treated culture, are able to abolish established tumors in vivo without the need of IL-2 or
vaccine administration. Our preliminary data shows B cells treated with CpG have overt CD40 (costimulatory
protein) and concomitantly CD8+ T cells express CD40L. We found that at this time CD8+ T cells acquire a T
follicular memory-like (TFML) phenotype denoted by CXCR5, ICOS, and PD-1 expression. We posit that CD40
signaling in B cells post CpG-treatment is responsible for the development of CD8+ TFML cells and potentiated
antitumor activity. CD8+ T cells generated from CpG-treated cultures gain a unique phenotype denoted by high
expression of the IL-2 cytokine receptor IL-2R¿ and dim expression of CD39¿ My co-mentor Dr. Mark Rubinstein
recently published the importance of the IL-2R¿ in promoting engraftment of T cells in an ACT model.
Conversely, CD39 which is only minimally expressed on CpG-generated T cells compared to vehicle treated T
cells, is a marker associated with “terminally exhausted” CD8+ T cells in viral and cancer models. Thus, I seek to
study the mechanisms underlying how CpG induces this potent cell product and the roles of IL-2R¿ and CD39
in achieving robust antitumor responses. Overall, I hypothesize that TLR9 agonist CpG activates B cells in an
antitumor T cell culture, promoting T cells to be imprinted with a TFML phenotype via CD40 signaling in B cells. I
will examine this idea in Aim 1. Moreover, I posit that IL-2R¿ and CD39, inversely regulated by TLR9 signaling,
are responsible for augmenting the antitumor properties of adoptively transferred CD8+ T cells. This concept will
be analyzed in Aim 2. Uncovering how B cells can be activated by CpG to become potent antigen presenting
cells to CD8+ T cells in Aim 1 will establish a new paradigm for cancer therapy with Toll-like receptor agonist
CpG. Also, findings from these studies will provide insight into the generation of T cells with strong immunological
memory to tumors and will have important clinical implications for patients with cancer. Overall, the proposed
research is expected to demonstrate that activation of the TLR9 pathway with CpG may sufficiently induce
durable immunity against the growth and recurrence of advanced tumors.