WEHI Wednesday Seminar hosted by Associate Professor Marie-Liesse Labat

 

Dr Clare Weeden

Research Officer - Labat & Gray Labs, Personalised Oncology & Immunology divisions

 

Immune pressure on lung tumour evolution: a tale of two cancers





Online seminar access via Slido and enter code #WEHIWednesday

Including Q&A session

 

As many as 25% of lung cancer cases occur in people without a history of cigarette smoking, rendering lung cancer in never-smokers the seventh leading cause of cancer death in the world. Lung cancers arising in ever-smokers (ES) and never-smokers (NS) can be viewed as distinct diseases with major clinical differences, including poorer responses to immunotherapies in NS patients. It is currently unknown how lung cancers are influenced by the ‘soil’ in which they arise. We hypothesised the immune environment within the lung, particularly tissue-resident memory T cells (TRM), constitutes a selective pressure upon tumour evolution in a discrete manner between ES and NS patients. We used mass cytometry or CyTOF to deeply profile the immune landscape in non-malignant lung tissue, early-stage primary tumours and late-stage primary tumours in never-smoker (NS) and ever-smoker (ES) patients.

We discovered reduced immunosurveillance by TRM in the lung tissue of NS compared with ES lung TRM and that these T cells failed to readily activate after stimulation. Similarly, in early-stage tumours from NS patients, CD8+ T cells had significantly reduced activity, even when compared to CD8+ T cells in ES tumours with similar tumour mutational burden. To assess the impact of these distinct immune selective pressures on tumour immunogenicity and evolution, we used sequencing data of lung cancers from multiple sites to infer the timing of molecular events in tumour evolution. We detected early tumour immune escape processes only in ES patients, resulting in lower frequencies of shared neoantigens. In contrast, the reduced immune pressure in NS patients generated less immune escape events and a greater proportion of patients with high frequencies of shared neoantigens.

How can we overcome the problem of the quiescent immune environment in NS lung cancer patients? We found that activating the T cell co-stimulatory molecule, ICOS, with an agonist antibody could reduce tumour burden in mice bearing lung adenocarcinomas. This agent promoted enhanced T cell proliferation in NS lung T cells regardless of T cell receptor engagement.  Overall, our work supports a model where a lack of TRM immunosurveillance and activity in NS tumours correlates with low selective pressure to evade the host immune system. The resulting T cell quiescence and clonal neoantigens within NS tumours creates an opportunity for alternative immunotherapies targeting T cell co-stimulatory molecules to promote anti-tumour immunity in these patients.