Endothelial cell anergy

Endothelial cell anergy is a condition during the process of angiogenesis,^[2] where endothelial cells, the cells that line the inside of blood vessels, can no longer respond to inflammatory cytokines.^[3][4] These cytokines are necessary to induce the expression of cell adhesion molecules to allow leukocyte infiltration from the blood into the tissue at places of inflammation, such as a tumor. This condition, which protects the tumor from the immune system, is the result of exposure to angiogenic growth factors.

Vasculature-based immune suppression mechanisms. Tumor endothelial cell anergy is represented by the suppression of endothelial adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin. The tumor vasculature contributes to more immune suppression through enhanced expression of immune checkpoint molecules, such as PD-L1 and IDO, that suppress the function of leukocytes. In addition, the tumor vasculature expresses molecules, such as FASL and galectin-1, that can give death signals to leukocytes.^[1]

Next to endothelial cell anergy, there are more vascular mechanisms that contribute to escape from immunity, such as the expression of immune checkpoint molecules (e.g. PD-L1/2) and proteins that can deliver death signals in leukocytes (Fas ligand and galectin-1).

Leukocyte infiltration

The formation of a leukocyte infiltrate at places of inflammation is dependent on the interaction of leukocytes in the blood with the vascular wall. This interaction and leukocyte extravasation is mediated by cell adhesion molecules on both leukocytes and endothelium. The endothelial cells normally express low levels of adhesion molecules, but at places of inflammation these adhesion molecules become expressed due to the exposure to inflammatory cytokines, such as interleukin 1, interferon gamma and tumor necrosis factor alpha.

Angiogenesis blocks leukocyte infiltration

Endothelial cell anergy was first described in 1996 when it was shown that endothelial cells in a tumor are not able to upregulate the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (CD62E), as a result from exposure angiogenic stimulation by e.g. vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF).^[3][4] The result of endothelial cell anergy in a tumor is that leukocytes will not be able to reach the tumor, resulting in hampering of the anti-tumor immune response. Next to induction of endothelial cell anergy, ongoing angiogenesis is immunosuppressive at multiple levels.^[5]

Anti-angiogenesis overcomes endothelial cell anergy and improves immunotherapy

Since this form of immune suppression is mediated by angiogenic stimulation, it was shown that anti-angiogenic therapy could revert endothelial cell anergy, allow leukocytes to infiltrate tumors and stimulate anti-tumor immunity.^[6][7] Overcoming endothelial cell anergy underlies the current success of clinical treatment of cancer with a combination of anti-angiogenic therapy and immunotherapy, mainly immune checkpoint blockade.^[8][1]

An embryonic program

It has been suggested that endothelial cell anergy also occurs during embryonic stages to allow efficient development of the embryo under immune silent conditions and help protecting the embryo from the maternal immune response. Tumors have hijacked this process to grow under the support of endothelial cell anergy mediated immune suppression.^[9]

History

The concept of endothelial cell anergy was introduced by Griffioen and coworkers in 1996.^[1]

References

1. Huinen ZR, Huijbers EJ, van Beijnum JR, Nowak-Sliwinska P, Griffioen AW (August 2021). "Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes". Nature Reviews. Clinical Oncology. 18 (8): 527–540. doi:10.1038/s41571-021-00496-y. PMID 33833434. S2CID 233187995.
2. Dudley AC, Griffioen AW (April 2023). "Pathological angiogenesis: mechanisms and therapeutic strategies". Angiogenesis. 26 (3): 313–347. doi:10.1007/s10456-023-09876-7. PMC 10105163. PMID 37060495.
3. Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G (March 1996). "Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors". Cancer Research. 56 (5): 1111–1117. PMID 8640769.
4. Griffioen AW, Damen CA, Blijham GH, Groenewegen G (July 1996). "Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium". Blood. 88 (2): 667–673. doi:10.1182/blood.V88.2.667.bloodjournal882667. PMID 8695814. S2CID 35620015.
5. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK (May 2018). "Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges". Nature Reviews. Clinical Oncology. 15 (5): 325–340. doi:10.1038/nrclinonc.2018.29. PMC 5921900. PMID 29508855.
6. Dings RP, Vang KB, Castermans K, Popescu F, Zhang Y, Oude Egbrink MG, et al. (May 2011). "Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer". Clinical Cancer Research. 17 (10): 3134–3145. doi:10.1158/1078-0432.CCR-10-2443. PMC 4242153. PMID 21252159.
7. Nowak-Sliwinska P, van Beijnum JR, Griffioen CJ, Huinen ZR, Sopesens NG, Schulz R, et al. (May 2023). "Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy". Angiogenesis. 26 (2): 279–293. doi:10.1007/s10456-022-09863-4. PMC 10119234. PMID 36459240.
8. Khan KA, Kerbel RS (May 2018). "Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa". Nature Reviews. Clinical Oncology. 15 (5): 310–324. doi:10.1038/nrclinonc.2018.9. PMID 29434333. S2CID 4957378.
9. Huijbers EJ, Khan KA, Kerbel RS, Griffioen AW (January 2022). "Tumors resurrect an embryonic vascular program to escape immunity". Science Immunology. 7 (67): eabm6388. doi:10.1126/sciimmunol.abm6388. PMID 35030032. S2CID 245933926.