CST 2015 / poster-tumor-immunology
.pdfTumor Immunology
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T cell |
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CD4+ |
B cell |
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DC |
Immune |
T cell |
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T cell |
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Checkpoint |
priming |
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IL-2, 4, 5 |
TNF-α |
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Tumor-draining Lymph Node |
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DC |
IL-1β |
Mast cell |
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Proliferation and production |
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Tumor-promoting |
MMPs |
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of anti-tumor antibodies |
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Macrophage |
TGF-β |
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MMPs |
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Tumor-specific |
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IL-6 |
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VEGF |
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Angiogenesis |
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CD8+ T cell |
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MMPs |
IL-13 |
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Activation/Response Change |
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MSC |
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IL-4 |
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TReg |
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M2 |
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Arginase |
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IL-10 |
Th2 |
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Macrophage |
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FoxP3 |
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TIM-3 |
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PD-1 |
TCR |
TGF-β |
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CD4+ |
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CCL22 |
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IL-10 |
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Inflammation |
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IL-1β |
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IFNγ |
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TGF-β |
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TNF-α |
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NK |
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IL-10 |
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TGF-β |
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T-bet |
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IL-35 |
IFNγ |
CTL |
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cytotoxic |
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M1 |
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granules |
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Th1 |
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T-bet |
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cytotoxic |
Macrophage |
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T-bet |
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granules |
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IL-2 |
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Galectin-9 |
-B7H3 |
-B7H4 |
PD-L1 |
MHC |
TNF-R |
IL-6R |
IL-1β |
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TNF-α |
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TNF-α |
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IFNγ-R |
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Jak3 |
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ALK |
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ROS1 |
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MMPs |
CCL22 |
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Class I antigen |
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Jak |
RTK: EGFR |
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VEGF |
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NF-κB |
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HER2 |
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presentation; |
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Stat1 |
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etc. |
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T cell apoptosis |
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IDO; PD-L1 |
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Stat3 |
oncogenic |
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signaling |
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Akt |
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IL-10 |
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Genes of cell growth and survival; |
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Stat3 |
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IDO |
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PD-L1, VEGF, IL-6, IL-10 |
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MAPK |
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Nucleus |
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Tumor Cell |
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© 2014 Cell Signaling Technology, Inc.
Pathway Diagram Key |
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Tentative Stimulatory Modification |
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Direct Stimulatory Modification |
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Direct Inhibitory Modification |
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TIM-3 |
B7-H3 |
CTLA-4 |
PD-1 |
TCR |
ICOS |
OX40 |
CD40 |
CD27 |
CD137 |
CD28 |
Galectin-9 |
B7-H4 |
CD80, 86 |
PD-L1 |
MHC |
ICOSL |
OX40L |
CD40L |
CD70 |
CD137L |
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Tumor cells employ multiple defense strategies to evade detection by the immune system. One common strategy, upregulation of immune checkpoint proteins and ligands, takes advantage of a natural immune mechanism for self-tolerance and prevention of collateral tissue damage (1,2). Immune checkpoint proteins, such as PD-1, CTLA-4, and many others, are located on T cells and engage with their corresponding ligand on tumor cells or dendritic cells, sending inhibitory signals that repress T cell activation or response (1,2). One of the first discovered checkpoint proteins, CTLA-4, plays a role at the stage of T cell priming by binding to the CD28 ligands CD80 or CD86 to prevent co-stimulatory signals necessary for T cell activation (1). In contrast, the PD-1/PD-L1 checkpoint acts later in the process, inhibiting anti-tumor immune responses by effector T cells such as CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lympho-
cytes (CTLs), leading to decreases in IFNγ production and cytolytic activity (1). Upregulation of PD-L1 expression on the tumor cell surface is mediated by IFNγR signaling to Stat1, as well as oncogenic signaling through several receptor tyrosine kinases (EGFR, ALK, ROS, HER2, and others) to activate the MAPK, Akt, and Stat3 pathways (1–3).
Cells in the tumor microenvironment can also influence tumor progression. FoxP3+/CD4+ T regulatory cells (TRegs) and myeloid-derived suppressor cells (MSCs) secrete immunosuppressive cytokines IL-10 and TGF-β to inhibit the activity of Th1 cells and CTLs (1,2,4). Natural killer (NK) cells release cytotoxic granules against the tumor cell and secrete IFNγ, which stimulates surrounding pro-inflammatory M1 macrophages (5). Pro-tumorigenic M2 macrophages sup-
press anti-tumor immune responses via production of IL-10 and TGF-β and promote metastasis through release of MMPs (4,6). MMPs and TGF-β are also released by surrounding mast cells (7).
Select Reviews:
1.Pardoll, D.M. (2012) Nat. Rev. Cancer 12, 252–264.
2.Vanneman, M. and Dranoff, G. (2012) Nat. Rev. Cancer 12, 237–251.
3.Kawakami, Y., Yaguchi, T., and Park, J.H., et al. (2013) Front. Oncol. 3, 136.
4.Elinav, E., Nowarski, R., and Thaiss, C.A., et al. (2013) Nat. Rev. Cancer 13, 759–771.
5.Mentlik, J.A., Cohen, A.D., and Campbell, K.S. (2013) Front. Immunol. 4, 481.
6.Gajewski, T.F., Schreiber, H., and Fu, Y.X. (2013) Nat. Immunol. 14, 1014–1022.
7.Krstic, J. and Santibanez, J.F. (2014) Scientific World Journal 521754.
We would like to thank Girija Goyal, Susanne Baumeister, M.D., Karrie Wong, Ph.D., and Glenn Dranoff, M.D. (Dana-Farber Cancer Institute and Harvard Medical School) for reviewing this poster.
For Research Use Only. Not For Use in Diagnostic Procedures. © 2014 Cell Signaling Technology, Inc., Cell Signaling Technology® is a registered trademark of Cell Signaling Technology, Inc.
www.cellsignal.com/pathways | www.cstj.co.jp
14PSTCORPCANR0132ENG_00