| dc.description.abstract | Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) is the most frequent
subtype of lymphoma with approximately 4,800 new cases per year in the UK. Although it is
a curable disease with standard immunochemotherapy, up to one third of patients are
primary refractory or relapse after a period of remission. Until recently the prognosis for
these patients was extremely poor. The recent approval of chimeric antigen receptor T
(CAR-T) cell therapy has significantly improved the outlook for this group, however over half
of the patients treated will progress and many others will not be suitable due to rapid
disease progression. There are currently a multitude of new agents in development which
hold much promise and will likely improve the outlook further for the highest risk patients.
However, there remain several unmet needs including improved translation of biological
insights to directly benefit patient care.
Recent studies have focused on the genomic landscape in DLBCL, with new subgroups
proposed based on the presence of recurrent and potentially actionable mutations,
including many which facilitate escape from immune detection. In addition to molecular
signals from the malignant lymphoma cells, there are reproducible signals from the nonmalignant
compartment in both the tissue and peripheral blood microenvironment, with
relevance to disease biology. Considerable variation is seen in immune cell composition and
function between individuals in both health and disease, but this has not been well
characterised in DLBCL.
We focused predominantly on the peripheral blood immune compartment in this work,
confirming the presence of a relative monocytosis and lymphopenia in DLBCL and their
relevance to survival. We present a detailed description of the immune landscape in DLBCL,
and document disease and outcome associated immune signatures. We identify
mechanisms to account for these variations, widespread cytokine dysregulation and
multiple bases of immune dysfunction. We also establish monocytes as the main peripheral
blood source of cytokine production in DLBCL. Finally, we establish a pipeline for detailed
characterisation of the tissue immune microenvironment using imaging mass cytometry. | en_US |
