About 50 years ago, the enigma of Hodgkin's lymphoma was depicted as the Hodgkin maze in two editorials in The Lancet.The uncertainties of the time were expressed through two questions:
“Infection or neoplasm?” and “One entity or two (or more)?”.
Subsequently, advances in cell biology and molecular pathology provided
answers to these questions. Substantial evidence now indicates that
classical Hodgkin's lymphoma is a distinct neoplastic entity, with
heterogeneous pathological features, which might be associated with
Epstein-Barr virus infection. Cases with intermediate features between
classical Hodgkin's lymphoma and diffuse large B-cell lymphomas have
been recognised. Typically, rare Hodgkin and Reed-Sternberg (HRS) cells
are surrounded by immune and inflammatory cells, including T helper 2
cells and T regulatory cells.
HRS
cells express programmed cell death ligand (PD-L) 1 and 2, which bind
programmed cell death 1 (PD-1), a receptor expressed by T cells (figure).
Binding activates the PD-1 signal transduction pathway, which
inactivates tumour-specific T cells. The PD-L1–PD-1 pathway, therefore,
functions as a checkpoint that regulates T cell-mediated immune
responses. Through this mechanism, HRS cells escape immune surveillance
and thereby evade immune destruction.
Checkpoint-inhibiting
antibodies showed promising results in the treatment of relapsed or
chemotherapy-refractive classical Hodgkin's lymphoma, with durable
clinical responses in heavily pretreated patients, although their
tumours developed immune resistance.
The mechanisms of resistance to checkpoint-inhibiting antibodies have been partially identified in solid tumours,
but remain largely unknown in classical Hodgkin's lymphoma. These uncertainties mean that we are again in the Hodgkin maze, because of the disease's enigmatic tangle that includes inflammatory responses to HRS cells and Epstein-Barr virus, the aberrant phenotype of HRS cells, deregulated oncogenic pathways, immune escape, and tumor–host interface crosstalk (figure).
The mechanisms of resistance to checkpoint-inhibiting antibodies have been partially identified in solid tumours,
but remain largely unknown in classical Hodgkin's lymphoma. These uncertainties mean that we are again in the Hodgkin maze, because of the disease's enigmatic tangle that includes inflammatory responses to HRS cells and Epstein-Barr virus, the aberrant phenotype of HRS cells, deregulated oncogenic pathways, immune escape, and tumor–host interface crosstalk (figure).
We
can learn about the mechanisms of resistance to checkpoint blockade in
classical Hodgkin's lymphoma from progress in solid tumours. For
example, a preclinical study showed that resistance correlated with
infiltration of the tumour by immunosuppressive myeloid cells.
Therefore, to understand resistance to checkpoint blockade in classical Hodgkin's lymphoma, we should study the inflammatory and immune cells in the tumour microenvironment and the immunomodulatory proteins these cells express. This research is now possible using multiplexing immunofluorescence and immunohistochemistry, and digital image analysis.
Such research should reveal how to overcome drug resistance in classical Hodgkin's lymphoma through rational combinations of checkpoint inhibitors and cellular immunotherapy.
Therefore, to understand resistance to checkpoint blockade in classical Hodgkin's lymphoma, we should study the inflammatory and immune cells in the tumour microenvironment and the immunomodulatory proteins these cells express. This research is now possible using multiplexing immunofluorescence and immunohistochemistry, and digital image analysis.
Such research should reveal how to overcome drug resistance in classical Hodgkin's lymphoma through rational combinations of checkpoint inhibitors and cellular immunotherapy.
Ref.
Carey CD, Gusenleitner D, Lipschitz M et al.
Carey CD, Gusenleitner D, Lipschitz M et al.
Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma.
Blood. 2017; 130: 2420-2430View
in Article
31867-1&id=gr1.jpg){kind=link}
Inga kommentarer:
Skicka en kommentar