Date of Award
Medical Doctor (MD)
Oscar R. Colegio
Keratinocyte carcinomas (KC) are the most commonly diagnosed malignancies. The process of KC tumorigenesis is a multi-step progression involving genetic alterations and immune hijacking. We were able to elucidate the role of the macrophage in the tumor microenvironment, inhibit the tumor-associated macrophages (TAM) to decrease tumorigenesis, and use clinical data to infer the crucial relationship between the immune system and genetics in KC.
Using basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) obtained in clinical practice, we were able to determine that the more indolent BCC had fewer TAM that were less pro-tumorigenic compared to SCC. TAM express arginase, an enzyme of the urea cycle that is a marker and effector molecule of pro-tumorigenic macrophages. We used a small molecule inhibitor of arginase to inhibit TAM in a novel model of SCC in mice, and were able to significantly decrease the rate of tumorigenesis. Arginase inhibition resulted in more tumor-infiltrating T cells and dendritic cells, and combination therapy with PD-1 inhibition had synergistic effects in decreasing tumor growth.
Finally, using retrospective chart review data of solid organ transplant recipients (SOTR), we were able to determine that the novel immunosuppressant belatacept decreased risk of SCC development in SOTR compared to calcineurin inhibitors (CNI). Given that CNI has direct DNA-damaging effects, and belatacept immunosuppression results in similar clinical transplant outcomes, this further reinforces the interplay between the immune system and genetics in the development of KC.
Wang, Mike, "Keratinocyte Carcinomas - The Interplay Between Genetics And The Immune Microenvironment" (2020). Yale Medicine Thesis Digital Library. 3963.