Identifying tumour-immune interactions as determinants of clinical sequelae in chronic lymphocytic leukaemia

Background: The immune system possesses anti-tumour capabilities that can be harnessed to eradicate cancer. However, it is currently unknown what aspects of anti-tumour immunity determine tumour fate.

Chronic lymphocytic leukaemia (CLL) is a model disease to address this, with a clinical spectrum ranging from rapid disease progression to spontaneous tumour regression.

Understanding the differences in tumour-immune interactions between spontaneously regressing and progressing CLL could elucidate immune mechanisms critical for tumour control.

Additionally, these mechanisms could potentially influence therapeutic response and contribute to the maintenance of long-term remission after CLL treatment.

Aims: This study aims to uncover important anti-tumour immune features and tumour-immune interactions through a comparative study of intrinsic tumour immunogenicity and the extrinsic immune microenvironment in spontaneously regressing versus progressing CLL.

Moreover, it aims to evaluate whether these same features and interactions underlie differences between patients with durable response to CLL treatment and others with short-lived or suboptimal response.

Methods: As a measure of tumour immunogenicity, the repertoire of functionally immunogenic tumour antigens will be compared between spontaneously regressing and untreated progressing CLL (n=20 each).

This will involve characterisation of the tumour antigenic landscape in each CLL through analysis of the major histocompatibility complex (MHC) class I and II immunopeptidome, complemented by proteogenomic analysis, with the functional immunogenicity of identified neoantigens assessed by their capacity for T-cell induction ex vivo.

Comparison of the tumour immune microenvironment between these two CLL groups will be undertaken through genome-scale, time-resolved single-cell analysis of longitudinal peripheral blood samples from representative CLL cases (n=5 per comparator group), complemented by lymph node and bone marrow aspirate samples.

Through comparing the evolutionary trajectory of immune cell states and tumour-immune interactions during spontaneous regression and progression, and any underlying clonotypic or epigenetic changes, key putative mechanisms underpinning effective tumour control will be identified and functionally validated.

As further independent validation, the most significant of these mechanisms will be evaluated in patients receiving treatment with chemoimmunotherapy (n=200) or the ibrutinib/venetoclax combination (n=60) within UK CLL clinical trials, to assess changes during therapeutic response and CLL relapse, and to determine whether they influence minimal residual disease response kinetics and long-term treatment outcome.

How the results of this research will be used: Results from this research will have translational potential beyond CLL, generating novel immunotherapeutic targets and providing a basis for designing future cancer immunotherapies, as well as yielding novel predictive biomarkers of response to cancer treatments and long-term outcome.