Lenalidomide Polarizes Th1-specific Anti-tumor Immune Response and Expands XBP1 Antigen-Specific Central Memory CD3+CD8+T cells against Various Solid Tumors.
BACKGROUND
Effective combination immunotherapeutic strategies may be required to enhance effector cells' anti-tumor activities and improve clinical outcomes.


METHODS
XBP1 antigen-specific cytotoxic T lymphocytes (XBP1-CTL) generated using immunogenic heteroclitic XBP1 US184-192 (YISPWILAV) and XBP1 SP367-375 (YLFPQLISV) peptides or various solid tumor cells over-expressing XBP1 target antigen were evaluated, either alone or in combination with lenalidomide, for phenotype and immune functional activity.


RESULTS
Lenalidomide treatment of XBP1-CTL increased the proportion of CD45RO+memory CD3+CD8+ T cells, but not the total CD3+CD8+T cells. Lenalidomide upregulated critical T cell activation markers and costimulatory molecules (CD28, CD38, CD40L, CD69, ICOS), especially within the central memory CTL subset of XBP1-CTL, while decreasing TCRαβ and T cell checkpoint blockade (CTLA-4, PD-1). Lenalidomide increased the anti-tumor activities of XBP1-CTL memory subsets, which were associated with expression of Th1 transcriptional regulators (T-bet, Eomes) and Akt activation, thereby resulting in enhanced IFN-γ production, granzyme B upregulation and specific CD28/CD38-positive and CTLA-4/PD-1-negative cell proliferation.


CONCLUSIONS
These studies suggest the potential benefit of lenalidomide treatment to boost anti-tumor activities of XBP1-specific CTL against a variety of solid tumors and enhance response to an XBP1-directing cancer vaccine regime.
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Jooeun
J
Bae
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Derin B
DB
Keskin
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Kristen
K
Cowens
Weill Cornell Medical College, New York, NY, USA.
Ann-Hwee
AH
Lee
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Glen
G
Dranoff
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; VA Boston Healthcare System, Boston, Massachusetts, USA.
Nikhil C
NC
Munshi
Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Kenneth C
KC
Anderson
Antigen-specific cytotoxic T lymphocytes; Cancer vaccine; Combination immunotherapy; Lenalidomide; XBP1
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