Reprogramming myeloid cell-mediated immunosuppression in lung cancer microenvironment

There are a number of promising immunotherapeutic agents becoming available for the treatment of cancer. Some of these, known as immune checkpoint inhibitors, can trigger remarkable clinical responses. They unleash tumour-specific T cell activities, and exert a systemic anti-tumour effect that can be powerful. However, success seems limited to only a proportion of patients. Autoimmune-type side effects can be severe and the treatment is very expensive. It is crucially important that the treatment is applied in a personalised manner, and we need to identify patients who are most likely to benefit.

One of the possible reasons behind treatment failure is that the cancer microenvironment in some individuals exerts dominant immune-suppressive effects, preventing effector T cell function. Our aims are: (1) Identifying tumours in patients with lung cancer that exhibit strong immune-suppression; (2) Identifying the nature of localised immunosuppression; (3) Counteracting localised immune- suppression. The latter would be expected to boost response rates in a larger proportion of patients to immunotherapy. We will perform some fundamental studies to model the cancer tissue and its full complexity in order to fully achieve these aims.

Our proposal involves developing an ex vivo tissue-model of the lung cancer microenvironment, based on whole-tissue explant cultures that fully capture the multicellularity and complex architecture of the original cancer. We will add autologous myeloid cells to this system, and determine the influence of the tumour-environment on their function (cell motility/tissue penetration, cytokine secretion profiles, antigen presentation and T cell stimulation). We will also apply pressures to the system using reagents that modify myeloid and T cell behaviour via targeting stromal and tumour cells. A number of immune-modifying reagents are currently available to do this, and through collaborations with industrial partners new agents are accessible.

One of the major aims is to understand the molecular determinants of a suppressive tissue. We will use an RNA-profiling technology to examine levels of overexpressed immunologically relevant transcripts in the tissues. This will be done before or after the addition of the immune modifying reagents. The RNA-profile will be examined for correlations with immune-function. The same analysis will be carried out on exosome-vesicles present in the tissue-secretome. This approach has not been tested previously but has the potential of leading to a novel, non-invasive liquid biopsy of the tissue providing information predicting immune-responsiveness.

The study will provide much needed insight into molecular factors dictating immunological responsiveness in lung cancer. It will generate information helpful in overcoming the main immunosuppressive elements, and to bolster the efficacy of checkpoint inhibitors. Lastly the study holds the potential for developing tissue or liquid sampling approaches amenable to predict response to immunotherapeutic agents, aiding patient stratification and treatment monitoring in future clinical trials.