Title: Understanding the tumour-supportive functions of endogenous TRAIL and LUBAC in the context of cancer immunotherapy
Funder: Cancer Research UK

Abstract: Background Immune checkpoint blockade (ICB) has emerged as a new paradigm in cancer therapy. However, not all cancer patients, including lung cancer patients, benefit from ICB. Thus, certain tumours evolved different or additional mechanisms of immune evasion. The TNF-related apoptosis-inducing ligand (TRAIL) is best known for its ability to specifically kill cancer cells. However, during this current funding period we discovered that the endogenous TRAIL/TRAIL-R system can play a tumour-promoting role. We found this system to be a crucial mediator of KRAS-driven tumour progression, invasion and metastasis. Additionally, TRAIL-apoptosis-resistant cancer cells can induce cytokine production, leading to the establishment of a tumour-supportive tumour microenvironment (TME). The cellular changes we detected suggest that TRAIL could be immuno-suppressive in the TME. Certain aspects of this immuno-suppression could be involved in the mechanisms that could be overcome by ICB whilst others may be independent thereof. During this current funding period we also found that TRAIL signalling, including TRAIL-mediated cytokine production and cell death, are regulated by the linear ubiquitin chain assembly complex (LUBAC). It is therefore possible that LUBAC may be required for certain tumour-supportive, including immuno-suppressive, roles triggered by TRAIL. As LUBAC is also involved in other immune signalling pathways, LUBAC might also influence tumour cell survival and tumour immunity independently of TRAIL. Aims In the proposed research programme we aim to understand the tumour biology of endogenous TRAIL and LUBAC in lung cancer and to which extent they depend on each other. In addition, we aim to decipher whether they are involved in the way ICB works or, alternatively, whether inhibition of TRAIL and/or LUBAC may synergise with ICB. Methods We will employ state-of-the-art in vitro and in vivo methodologies to assess the roles of the different factors we study in lung cancer. Specifically, we will use lung cancer mouse models which recapitulate human lung cancer and correlate our findings in these models to results obtained on tissue from lung cancer patients. How the results of this research will be used The results of the proposed research shall provide the scientific basis and rationale for the future application of TRAIL and/or LUBAC inhibition in cancer therapy, if possible in combination with ICB with the aim to overcome primary or secondary resistance to this new paradigm in cancer therapy.

Lay abstract: Background Immune checkpoint blockade (ICB) has emerged as a new paradigm in cancer therapy. However, not all cancer patients, including lung cancer patients, benefit from ICB. Thus, certain tumours evolved different or additional mechanisms of immune evasion. The TNF-related apoptosis-inducing ligand (TRAIL) is best known for its ability to specifically kill cancer cells. However, during this current funding period we discovered that the endogenous TRAIL/TRAIL-R system can play a tumour-promoting role. We found this system to be a crucial mediator of KRAS-driven tumour progression, invasion and metastasis. Additionally, TRAIL-apoptosis-resistant cancer cells can induce cytokine production, leading to the establishment of a tumour-supportive tumour microenvironment (TME). The cellular changes we detected suggest that TRAIL could be immuno-suppressive in the TME. Certain aspects of this immuno-suppression could be involved in the mechanisms that could be overcome by ICB whilst others may be independent thereof. During this current funding period we also found that TRAIL signalling, including TRAIL-mediated cytokine production and cell death, are regulated by the linear ubiquitin chain assembly complex (LUBAC). It is therefore possible that LUBAC may be required for certain tumour-supportive, including immuno-suppressive, roles triggered by TRAIL. As LUBAC is also involved in other immune signalling pathways, LUBAC might also influence tumour cell survival and tumour immunity independently of TRAIL. Aims In the proposed research programme we aim to understand the tumour biology of endogenous TRAIL and LUBAC in lung cancer and to which extent they depend on each other. In addition, we aim to decipher whether they are involved in the way ICB works or, alternatively, whether inhibition of TRAIL and/or LUBAC may synergise with ICB. Methods We will employ state-of-the-art in vitro and in vivo methodologies to assess the roles of the different factors we study in lung cancer. Specifically, we will use lung cancer mouse models which recapitulate human lung cancer and correlate our findings in these models to results obtained on tissue from lung cancer patients. How the results of this research will be used The results of the proposed research shall provide the scientific basis and rationale for the future application of TRAIL and/or LUBAC inhibition in cancer therapy, if possible in combination with ICB with the aim to overcome primary or secondary resistance to this new paradigm in cancer therapy.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS