The Immune Checkpoint Balance in Melanoma and Auto-Immunity

Kleinjan, J. (Jan) (2017) The Immune Checkpoint Balance in Melanoma and Auto-Immunity. thesis, Medicine.

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Abstract

Background. Immune checkpoints play a major role in regulating the immune response by providing co-stimulation or co-inhibition to T-cells. A disturbance of this regulation can result in ineffective immune responses, which can predispose to cancer and auto-immunity. Regulatory checkpoint pathways are engaged by tumors to prevent immune destruction. Blocking these regulatory pathways with immune checkpoint inhibitors potentiates T-cell responses. This results in effective anti-tumor responses, at the risk of inducing auto-immunity. Toxicity in checkpoint inhibition is very unpredictable. In this study we aimed to study the effects of the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab on immune checkpoint expression profiles in melanoma patients. Checkpoint expression profiles in melanoma patients are compared to patients with the auto-immune disease (giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)), and to healthy controls. We hypothesized that melanoma patients predominantly express regulatory checkpoints, whereas GCA/PMR patients have a relative lack of regulatory checkpoints. We expected that pembrolizumab therapy would result in a relative increase of co-stimulatory checkpoints. Methods. 8 melanoma patients were prospectively included before treatment with pembrolizumab. Expression of CD28, ICOS, VISTA, PD-1, CTLA-4 and CD40L on T-cells was measured before-, and after three weeks of treatment. Pre-treatment checkpoint expression profiles were compared to 8 sex- and age-matched healthy controls and 8 GCA/PMR patients in remission and on treatment. A pilot experiment was performed to analyse functional results of pembrolizumab treatment in vitro. Results. Immune checkpoint expression levels are highly variable in patients and healthy controls, and are differentially affected by pembrolizumab treatment in melanoma patients. Melanoma and GCA/PMR patients have an overall lower expression of both co-stimulatory and inhibitory checkpoints compared to healthy controls. Conclusion. The balance between co-stimulatory and co-inhibitory checkpoints is set differently in every person. Melanoma patients and GCA/PMR patients in remission have a comparable immune checkpoint expression profile. A disturbed expression of immune checkpoints predisposes to pathologic immune reactions, which can result in either melanoma or GCA/PMR.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervisor: and Brouwer, dr. E. and internist / rheumatologist and Institution: University Medical Center Groningen and Department: Rheumatology and Clinical Immunology
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:48
Last Modified:	25 Jun 2020 10:48
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/971

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