Abrogation of CD4 driven autoimmunity associated with tumour immunotherapy while preserving anti-tumour CD8 mediated immunity

Nawaf, Maher Ghaneim (2016). Abrogation of CD4 driven autoimmunity associated with tumour immunotherapy while preserving anti-tumour CD8 mediated immunity. University of Birmingham. Ph.D.

Nawaf16PhD.pdf
PDF - Accepted Version
Restricted to Repository staff only until 1 January 2025.
Download (4MB) | Request a copy

Abstract

In human, cancer immunotherapeutic strategies using blocking antibodies anti-CTLA-4 and anti-PD-1 have achieved significant clinical responses. However, this has been associated with significant off target toxic autoimmune side effects that have restricted dose escalation efficacy of these therapies. Previous work in our lab generated a FoxP3K0 mouse model without FoxP3+ dependent CD4 driven autoimmunity when the TNFRSF receptors OX40 and CD30 signals are abrogated simultaneously. Thus suggests a novel approach which can be applied to abrogate off target CD4 driven side effects in cancer immunotherapy, without compromising CD8 anti-tumour immune responses. Here we showed that the CD30K0 0X40KO FoxP3K0 (tKO) mice are resistant to tumour progression in a mouse model of melanoma where anti-tumour immunity is CDS dependent. This was mimicked in CD30K0 0X40K0 (dKO) mice and WT mice treated respectively with anti-CTLA-4, anti-PD-1, or anti-CTLA-4, anti-PD-1 and anti-OX40L and anti-CD30L blocking mAbs. Interestingly, the CD4 driven autoimmunity has been abrogated using the fourfold combination: anti-(CTLA-4, PD-1. OX40L and CD30L), while an excellent CD8 anti-tumour response is preserved in C57BI/6 mice harbouring melanoma tumours.
I have also investigated the effects of overexpression of IFNy in our mouse model of melanoma, using sanroque
mice that show IFNy overexpression phenotype. I have shown that tumours do grow more slowly in sanroque
mice. A striking finding in sanroque mice was that PD1 expression on tumour infiltrating CD4 and CD8 T cells
was virtually completely abrogated, indicating that this might explain the delayed tumour growth. I found that
agonistic OX40 mAbs in WT mice also downregulated PD-l expression on tumour infiltrating CD4 and CD8 T cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):