The Achilles’ heel of immune checkpoint blockade: Uncovering mechanisms of immune exclusion that drive resistance
Year: 2026
Type: dissertation
Abstract: Melanoma can affect various tissues, including the skin and the eyes. immune checkpoint inhibitors have revolutionized the treatment of many cancers, including metastatic melanoma, but uveal melanoma remains largely unresponsive, mainly due to low mutational burden. Changes in the tumor microenvironment composition can also impact immune checkpoint inhibitors’ efficacy. Moreover, genetic and epigenetic alterations in cancer cells and cells of the tumor stroma can impair T-cell priming and infiltration, further compromising the effectiveness of immune checkpoint inhibitors. Therefore, many cancer patients fail to respond or eventually develop resistance to this treatment option. This doctoral thesis investigates mechanisms of immune exclusion and resistance to immune checkpoint inhibitors in uveal and cutaneous melanoma. The first part of the thesis explores how loss of adipophilin underlies immunosuppression in uveal melanoma. Alongside BAP1 deficiency, loss of adipophilin leads to metabolic reprogramming, promoting immunosuppression. The second part of the thesis investigates CD74, chaperone of MHC-II, in melanoma progression and its potential in regulating dendritic cell functions. This study demonstrates that CD74 deficiency enhances antitumor immunity by modulating dendritic cell migration and improving cancer cell-specific antigen cross-presentation to T cells. By elucidating the role of adipophilin in uveal melanoma and uncovering the effects of CD74 depletion in enhancing dendritic cell functions in cutaneous melanoma, this thesis reveals novel mechanisms of immune regulation. Altogether, these findings suggest potential therapeutic targets that could enhance the efficacy of immune checkpoint inhibitors in refractory tumors.
Source: UTUPub (University of Turku)
Author: Maranou, Eleftheria
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Turun Yliopisto
OpenAlex ID: W7220766346