PhD defence L. (Lisanne) Noordam

Summary:

The aim of this thesis was to improve the treatment of cancer by manipulation of the immune system. In chapters 2 and 3 the effects of several immune checkpoint inhibitors and stimulators were evaluated on T cells isolated from several types of cancer. Blockade of the inhibiting immune checkpoint receptors LAG3 and PD-L1 promoted the ex vivo capacities of intra-tumoral T cells isolated from liver metastases of mismatch repair proficient colorectal carcinomas. In the proof-of-concept study, described in Chapter 3, the biclonic CD137xPD-L1 antibody stimulated proliferation of intratumoral T cells isolated from hepatocellular carcinoma samples. In chapters 4 and 5 a vaccination strategy was explored; in chapter 4 a panel of 12 tumor antigens was found to be expressed in the majority of hepatocellular carcinoma patients and in chapter 5 the immunogenicity of several of these antigens was explored. Interestingly, the expression of tumor antigens in adjacent macroscopically tumor-free tissues was a predictive factor for tumor recurrence. Finally, the effect of low-dose cyclophosphamide on circulating regulatory T cells was evaluated in patients synergistically treated with dendritic cell therapy, as a manner to reduce the immunosuppressive environment and tip the balance.