Biology subjects

Ambler, R.

Publications and source records attributed to Ambler, R..

3 recordsLinked to original sources

bioRxiv2021

Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harbouring KRASG12C mutations, but drug resistance frequently develops. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect anti-tumour immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterised how KRASG12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition upregulates interferon signaling via Myc inhibition, leading to reduced tumour infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumour model. KRASG12C inhibition fails to sensitize cold tumours to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs. One sentence summaryKRAS inhibition mobilizes anti-tumour immunity in immunogenic lung cancer models through derepressing interferon signaling via repression of Myc.

cancer biology↗

bioRxiv2021

The adenosine 2a receptor and TIM3 directly inhibit killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization

Tumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8+ cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2a receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2a receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this focus on CTL killing, blocking A2aR and TIM3 complements therapies that enhance T cell priming, e.g. anti-PD1 and anti-CTLA-4.

immunology↗

bioRxiv2018

PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor

CD8+ T cell killing of tumor cells is suppressed by the tumor microenvironment. Inhibitory receptors, prominently PD-1, are key mediators of this suppression. To discover cellular defects triggered by tumor exposure and associated PD-1 signaling, we have established an ex vivo imaging approach to investigate CD8+ tumor infiltrating lymphocytes (TILs) interacting with tumor targets. Whilst TIL:tumor cell couples formed effectively, couple stability deteriorated within 1-2 minutes. This was associated with excessive cofilin recruitment to the cellular interface, coincident deterioration of f-actin structures, increased TIL locomotion, and impaired tumor cell killing. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus suppresses TIL function by inducing a polarization-impaired state.

immunology↗