| Summary: | <p>Immune checkpoint inhibitor treatment has revolutionised treatment for cancers such as
malignant melanoma, producing durable responses in patients with metastatic malignancy.
Despite this progress, responses are still only seen in a subset of patients and the
phenotype and specificity of the T cells responsible for determining efficacy remain poorly
characterised. A better understanding of T cell behaviour during immunotherapy treatment
is required to identify markers of response and resistance and to predict effective
combination strategies. To address this, we performed longitudinal peripheral immune
monitoring of metastatic melanoma patients receiving checkpoint inhibitor therapy. By
integrating a variety of single-cell analysis approaches including mass cytometry, MHC
Class I tetramer staining, single-cell fluorescence activated cell sorting and single-cell RNAsequencing, we were able to track and analyse in detail tumour-specific T cell responses in
the periphery over time. Accumulation of activated effector CD8+ T cells expressing CD38
and HLA-DR was observed in response to treatment, was more pronounced with
combination anti-CTLA-4/anti-PD-1 treatment than anti-PD-1 monotherapy, and was
correlated with treatment outcome. Activated cells were enriched in tumour-specific
compared to microbial-specific T cells, with diversification and expansion of the tumour but
not microbial-specific response observed over the course of treatment. This was
accompanied by transient alterations in the functional avidity of T cell clones specific for the
common tumour-associated antigen MART-1. Single-cell RNA-seq revealed substantial
heterogeneity in the transcriptional profile of tumour-specific T cells during therapy with
transient activation and persistence of specific clonotypes observed. These results
demonstrate both the feasibility of monitoring tumour-specific T cells mobilised in response
to immunotherapy in the periphery, and provide insights into the mechanisms underpinning
therapeutic efficacy of combination checkpoint blockade. The results also have implications
for the identification of T cells and TCR clonotypes with maximum therapeutic potential for
other therapeutic strategies such as adoptive cell therapies.</p>
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