cd73 immune pathway - bristol-myers squibb€¦ · • targeting the cd73 pathway, in combination...

CD73 Immune Pathway CD73 CD39 A2aR Adenosine CD73 expressing cell T cell The CD73 pathway is just one of many immune pathways under investigation at Bristol-Myers Squibb. Learn more about our work in Immuno-Oncology by visiting: https://www.bms.com/life-and-science/science/immuno-oncology-pathway.html About CD73 CD73 is a cell surface enzyme which is overexpressed in the tumor microenvironment and promotes tumor growth by limiting anti-tumor immunity via the adenosine receptor pathway. 1,2 1 Kobie JJ, Shah PR,Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5’-adenosine monophosphate to adenosine. J Immunol. 2006;177(10):6780-6786. 2 Antonioli L,Yegutkin GG, Pacher P, Blandizzi C, Hasko G. Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer. 2016;2(2):95-109. 3 Whiteside TL. Targeting adenosine in cancer immunotherapy: a review of recent progress. Expert Rev Anticancer Ther. 2017;17(6):527-535. 4 Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107(4):1547-1552 CD73 and Immune Function • CD73 converts extracellular adenosine monophosphate (AMP) into immunosuppressive adenosine, which shuts down anti-tumor immune surveillance at the level of T and natural killer (NK) cells, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs). 2,3 CD73 and Cancer • In cancer, upregulation of CD73 expression in tumor cells and cells in the tumor stroma results in an increase in adenosine production, 2,3 which: - Inhibits T cell and NK cell cytotoxicity, cytokine production and proliferation as well as suppression of antigen- presenting cells (APCs). - Promotes regulatory T cell (Treg) proliferation and suppressive activity. - Stimulates MDSCs and macrophage M2 polarization. • These changes enable tumor growth and disease progression. Research Implications and Interactions • Preclinical research has identified CD73 as a contributor to immune escape in cancer, therefore, inhibition of CD73 activity may enhance anti-tumor immune surveillance at the level of T cells and other immune cells regulated by adenosine. 4 • Targeting the CD73 pathway, in combination with other potentially complementary immune pathways, may be a key strategy to help activate an anti-tumor immune response. Treg activity T cell function CD73 Tumor survival AMP Adenosine CD73 inhibition Treg activity Restored T cell function Anti-tumor response

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CD73 Immune Pathway

CD73

CD39

A2aR

Adenosine

CD73 expressing cell

T cell

The CD73 pathway is just one of many immune pathways under investigation at Bristol-Myers Squibb. Learn more about our work in Immuno-Oncology by visiting:

https://www.bms.com/life-and-science/science/immuno-oncology-pathway.html

About CD73CD73 is a cell surface enzyme which is overexpressed in the tumor microenvironment and promotes tumor growth by limiting anti-tumor immunity via the adenosine receptor pathway.1,2

1 Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5’-adenosine monophosphate to adenosine. J Immunol. 2006;177(10):6780-6786. 2 Antonioli L, Yegutkin GG, Pacher P, Blandizzi C, Hasko G. Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer. 2016;2(2):95-109. 3 Whiteside TL. Targeting adenosine in cancer immunotherapy: a review of recent progress. Expert Rev Anticancer Ther. 2017;17(6):527-535. 4 Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107(4):1547-1552

CD73 and Immune Function

• CD73 converts extracellular adenosine monophosphate (AMP) into immunosuppressive adenosine, which shuts down anti-tumor immune surveillance at the level of T and natural killer (NK) cells, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs).2,3

CD73 and Cancer• In cancer, upregulation of CD73

expression in tumor cells and cells in the tumor stroma results in an increase in adenosine production ,2,3 which:

- Inhibits T cell and NK cell cytotoxicity, cytokine production and proliferation as well as suppression of antigen-presenting cells (APCs).

- Promotes regulatory T cell (Treg) proliferation and suppressive activity.

- Stimulates MDSCs and macrophage M2 polarization.

• These changes enable tumor growth and disease progression.

Research Implications and Interactions

• Preclinical research has identified CD73 as a contributor to immune escape in cancer, therefore, inhibition of CD73 activity may enhance anti-tumor immune surveillance at the level of T cells and other immune cells regulated by adenosine.4

• Targeting the CD73 pathway, in combination with other potentially complementary immune pathways, may be a key strategy to help activate an anti-tumor immune response.

Treg activity

T cellfunction

CD73

Tumorsurvival

AMP

Adenosine

CD73 inhibition

Treg activity

RestoredT cell function

Anti-tumorresponse

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Severe active C3 glomerulonephritis triggered by immune ......complement pathway activation, while the second is believed to be associated with complement alternative pathway (AP)