Several current tumor immunotherapies (e.g., PD-1/PD-L1 blockade and tumor vaccine) are
designed to boost endogenous tumor-specific T cell responses. To improve the efficacy of
current immunotherapies and benefit more cancer patients, it is urgent to advance our
knowledge about the cellular and molecular mechanisms underlying the response of
endogenous tumor-specific T cells. Importantly, a subset of antigen-specific CD8 + T cells have
been identified as stem cell-like or progenitor-like, which are the ones responding to both PD-
1/PD-L1 blockade and tumor vaccine. However, we know little about how these stem-like T cells
respond to tumor vaccine.
Along a different line of research in mouse acute infection models, tissue-resident memory T
cells (T RM ) have been identified as a unique population of memory T cells. In contrast to other
migratory T cell subsets, T RM s do not re-circulate and reside inside a particular tissue (mostly
non-lymphoid tissues) for an extended period. We and others have established a critical role for
TGF-b in the establishment of T RM after acute infection. Our preliminary findings have
demonstrated that tumor draining lymph nodes (TDLNs) function as a unique reservoir to host
stem-like tumor-specific CD8 + T cells. Surprisingly, a substantial portion of these TDLN stem-like
T cells adopt a T RM phenotype in a TGF-b-dependent manner. Further, we have discovered that
wild type TDLN stem-like T cells rapidly, but transiently lose T RM phenotype after tumor vaccine.
In contrast, TGF-b receptor deficient TDLN stem-like T cells carry significantly reduced T RM
phenotype at baseline and exhibit greatly enhanced and prolonged response to tumor vaccine.
The enhanced response in TDLN is translated into increased migration from TDLN to tumor and
better tumor control for TGF-b receptor deficient CD8 + T cells. Importantly, inhibition of T cell
migration completely abolishes the response to tumor vaccine for TGF-b receptor deficient CD8 +
T cells. Together, our results support a working model that a significant portion of stem-like T
cells differentiate into T RM inside TDLN and will not migrate to tumor site. Loss of tissue-
residency is required for stem-like T cells to differentiate into migratory effectors and elicit robust
response to tumor vaccine. Suppression of tissue-residency in TDLN (e.g., deletion of TGF-b
receptor or TGF-b downstream molecular targets) will greatly boost the differentiation and
migration of stem-like T cells, which will lead to better tumor control in response to certain tumor
immunotherapies. In current proposal, we will directly test whether targeting TGF-b or T RM –
signature will boost the migration of stem-like T cells and therefore enhance the efficacy of
tumor vaccine as well as local irradiation released endogenous tumor antigen.