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When angiogenesis meets immunology

May 2023 Special Ariez

Renal cell carcinoma (RCC) is characterized by highly vascularized tumors that escape the immune system. What pathological mechanism is behind angiogenesis in renal cell carcinoma? How is the immune system involved in the onset and course of this disease? And what is the relationship between angiogenesis, VEGF and the immune system in RCC?

In this video, Dr Laurence Albiges, MD, PhD, Head of the Genitourinary Unit at Gustave Roussy, Villejuif, France, discusses the clinical and biological rationale for combining TKIs and IO in RCC. Dr. Albiges describes the pathophysiology of RCC and shares her thoughts on the preclinical evidence that supports this therapy combination and how this has translated into results in Phase III clinical trials.

Angiogenesis and VEGF, more than just the driver of renal cell carcinoma

Angiogenesis is a physiological process in which new blood and lymphatic vessels arise from the existing vascular bed under the influence of growth factors such as Vascular Endothelial Growth Factor (VEGF).1 New growth of blood vessels is a desirable effect in wound healing or embryogenesis. In the case of clear cell renal cell carcinoma (RCC), angiogenesis is pathological in nature and plays a crucial role in both the onset and progression of RCC.2

Renal cell carcinoma, angiogenesis-driven tumors with immunological traits2

It is well known that RCC is an angiogenesis-driven tumor in which the overexpression of pro-angiogenic growth factors such as VEGF is crucial.2 Let’s now have a look at the crossroads where angiogenesis and immunology meet.

Like VEGF-mediated angiogenesis, the immune system has an active role in how tumors develop, grow, and metastasize. Further, the interaction between angiogenesis and a muffled immune system seems to facilitate the development of tumors and their progression. Pro-angiogenic growth factors can directly affect immune cells. Or indirectly through the endothelium.3

Direct effect of angiogenesis on the immune system3

  1. VEGF induces a greater amount of checkpoints (PD-1 and CTLA-4) on immune cells, causing activated T cells to lose their function;
  2. VEGF increases the amount of myeloid-derived suppressor cells (MDSC) with immunosuppressive properties in the microenvironment of the tumor;
  3. VEGF prevents differentiation of stem cells into T cells, which negatively affects the adaptive immune system;
  4. VEGF prevents differentiation of monocytes into mature dendritic cells and therefore inhibits the innate immune system.

Indirect effect of angiogenesis on the immune system

The indirect effect occurs because pro-angiogenic factors make it difficult for immune cells to infiltrate the tumor by passing through the surface of endothelial cells. In this way, immune cells are facing denied access to tumors.3

The better understanding of the biological characteristics of RCC led to the approval of therapy targeting the VEGF pathway.2 Subsequently, combination of immunotherapy with targeted therapy has been approved allowing to simultaneously affect angiogenesis and the immune system.2

230387 – April 2023

Abbreviations

CTLA-4: cytotoxic T-lymphocyte associated protein 4; IO: Immuno-Oncology; MDSC: myeloid-derived suppressor cells; PD-1: programmed cell death protein 1; RCC: Renal cell carcinoma; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor.

References

  1. Teleanu, R. I., Chircov, C., Grumezescu, A. M., & Teleanu, D. M. (2019). Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment. Journal of Clinical Medicine, 9(1), 84. https://doi.org/10.3390/jcm9010084.
  2. Mennitto, A., Huber, V., Ratta, R., Sepe, P., de Braud, F., Procopio, G., Guadalupi, V., Claps, M., Stellato, M., Daveri, E., Rivoltini, L., & Verzoni, E. (2020). Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage? Journal of Clinical Medicine, 9(4), 930. https://doi.org/10.3390/jcm9040930.
  3. Rassy, E., Flippot, R., & Albiges, L. (2020). Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Therapeutic Advances in Medical Oncology, 12. https://doi.org/10.1177/1758835920907504.

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