Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

Abstract

Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag À/À mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies. Cancer Res; 71(3); 801-11. Ó2011 AACR.

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

“…S4 A and B). Increased expression of VCAM on tumor endothelial cells induced by 1D8 treatment of B16F10-OVA tumors growing in RAG −/− T-cell-deficient mice indicated an inflammatory phenotype induced by direct effects on endothelial cells (16). However, combined treatment did not alter transcription of CTL-attracting chemokines in WT mice compared with mice treated with OT-1 and control antibody (Fig.…”

“…(ii) CD137 is expressed on the endothelial cells of tumor vessels which, when stimulated in this location, enhances T-cell trafficking into tumors (16). In our case this mechanism appears dispensable for recruiting adoptively transferred T cells into tumors, but we observe higher numbers of endogenous CD8 + T cells, that are lost if the recipient mouse is CD137 −/− , indicating an effect of anti-CD137 therapy on endothelial cells and/or on the tumor homing capability of endogenous CD8 + T lymphocytes.…”

“…CD137 expression can also be induced on dendritic cells (15), tumor endothelial cells (16), B cells (17), and myeloid leukocytes (18) upon activation.…”

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

“…On the basis of these considerations, preliminary results in mice models suggest that combination therapies may be helpful in restoring an activating phenotype in the tumor microenvironment [71]. In experimental models combining B7-H1/PD-1 blockade with cancer vaccines [72][73][74][75], adoptive transfer of preactivated T cells, or T cell stimulation with anti-CD137 [76] often provides dramatic synergistic antitumor effects, in some cases eradicating well-established tumors.…”

Functional expression of CD137 (4-1BB) on T helper follicular cells

“…2,3 Tissue distribution is broader than originally described, as CD137 has also been found to decorate activated natural killer (NK) cells, 4,5 B cells, 6 dendritic cells (DCs), 7 myeloid precursors, 8 mastocytes, 9 and tumor capillary endothelial cells. 10 There is only one described ligand, namely CD137L or 4-1BBL, 11 which acts as an agonistic moiety that crosslinks 4-1BB giving rise to activation signals. CD137L is expressed on activated professional antigen presenting cells (APCs) such as activated B cells, macrophages and DCs.…”