Coupling of response biomarkers between tumour and peripheral blood in patients undergoing chemoimmunotherapy

Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers of clinical outcomes to guide treatment decisions. Here, we combine time-course RNA sequencing of peripheral blood mononuclear cells with pre-treatment tumour transcriptome data from the 54-patient cohort in the single arm phase II DREAM study. In peripheral blood, CD8 + T effector memory cells with stem-like properties are more abundant in responders at baseline, 3 weeks, and 6 weeks into therapy. These peripheral blood changes are linked to the transcriptional state of the tumour microenvironment. The identified immunological correlates are predictive of response and provide further evidence for the additive nature of the interaction between platinum-based chemotherapy and PD-L1 antibodies. Our study highlights the complex, but predictive interactions between the tumour and immune cells in peripheral blood during the response to chemoimmunotherapy. Overall design: 55 pleural mesothelioma patients were recruited from 8 Australian sites as a part of the phase II DREAM study. Patients were treated with up to 6 cycles of chemo-immunotherapy that included 3-weekly cisplatin or carboplatin in combination with pemetrexed and durvalumab. Maintenance included 12 months of durvalumab on a 4-weekly basis. Peripheral blood samples were drawn at three timepoints. The first was taken at pretreatment baseline prior to dexamethasone pre-medication (timepoint 0, BL). The subsequent two samples were taken before the second (timepoint 1, C2D1) and third cycles (timepoint 2, C3D1) of chemoimmunotherapy treatment. Single cell TCRseq was performed on the peripheral blood samples.