ABSTRACT
Spontaneous T cell pressure against an evolving tumor is a conserved mechanism of anti-tumor immune
control. On the other hand, immune therapies directed to alleviate paralyzing T cell dysfunction within solid
tumors only benefits a small proportion of patients with metastatic disease. The field is in desperate need for the
development of complementary therapies capable of enhancing sustained T cell-mediated control of primary and
metastatic tumor growth. However, myeloid cells within tumors present a substantial barrier towards overcoming
the immune dysfunction present in most cancers.
Here, we demonstrate that recognition of commensal bacteria through TLR5 signaling results in sustained
myeloid dysfunction and impaired response to PD-L1 blockade. TLR5 signaling broadly impairs myeloid function,
resulting in infiltration of tumors with poorly functional T cells. In TLR5 KO mice, PD-L1 blockade achieves
significantly increased overall survival and leads to durable and long-term remission for mice bearing aggressive
ovarian tumors. The effect of TLR5 signaling is recapitulated in non-responsive melanoma and breast tumor
models, suggesting that this signaling pathway is a conserved mechanism of immune suppression and failure
for PD-L1 blockade. Mechanisms underlying myeloid dysfunction and failure of PD-L1 blockade have largely
focused upon interactions between tumors and immune cells. However, our data implicate a mechanism
whereby recognition of commensal bacteria by TLR5-expressing immune cells initiates myeloid dysfunction and
failure of PD-L1 blockade. Based upon these data, inhibition of TLR5 signaling emerges as a means of restoring
anti-tumor T cell function across a broad range of tumor types. However, because TLR5 signaling is canonically
associated with activation of adaptive immunity in other settings, it is critical to understand how TLR5 signaling
impairs myeloid function within the tumor microenvironment.
The overarching goal is to define how commensal microorganisms impair anti-tumor immunity and response
to PD-L1 blockade. Here, we will test the hypothesis that chronic encounter with microbiome-derived TLR5
ligands and autocrine amplification of IL-6 polarize TLR5-expressing myeloid cells within the tumor
microenvironment (TME). This results in impaired ability of myeloid cells to prime and/or recall tumor-reactive T
cells and subsequent failure of PD-L1 blockade. Aim 1 will define how TLR5 signaling on myeloid cells affects
tumor growth and response to PD-L1 blockade. Aim 2 will determine how TLR5 signaling impairs myeloid
function. Aim 3 will leverage in vivo labelling of commensal microorganisms to establish how encounters between
commensal microorganisms and TLR5 expressing immune cells within the tumor microenvironment impair anti-
tumor immune function. Mechanistically, very little is known as to how the microbiome negatively impacts host
anti-tumor immune function. The studies proposed herein will fill this gap in knowledge, providing critical insight
into how host-microbiome crosstalk negatively impacts anti-tumor immunity and response to PD-L1 blockade.