Biphasic behavior of T cell subsets reflects failure of early anti-myeloma response and leads to progressive T cell dysfunction

TL;DR

A new mouse model reveals how T cell dysfunction progresses during multiple myeloma development, offering insights into early disease mechanisms and treatment testing.

Contribution

The study introduces a novel mouse model that captures the biphasic immune response and progressive T cell dysfunction in multiple myeloma.

Findings

The model shows biphasic behavior of T regulatory cells, Th17 cells, CD8+ T cells, and NK cells during myeloma progression.

Early anti-myeloma immune responses fail, leading to immunosuppression and CD8+ T cell exhaustion.

The model reflects human MM serological features and can be used to test new therapies.

Abstract

Multiple Myeloma (MM) progresses over 2-3 decades through two pre-malignant stages (MGUS and SMM), culminating in clinically active disease. Given the limitations in acquiring sequential bone marrow (BM) samples from patients over this time frame, the mechanisms that compromise immunosurveillance and promote the development of MM remain

Balb/c mice inoculated with MOPC315.BM myeloma cells were followed over the next 220 days. Blood and bone marrow samples were collected on days 80, 150, and 220 post cell inoculation. Blood samples were used to monitor levels of paraprotein and whole blood cell counts. BM aspirates were used for deep immune profiling by flow cytometry and for T cell function assays.

Blood analyses validated that the model reflects serological features of human MM. Analysis of BM samples revealed a biphasic behavior of T regulatory cells, Th17 cells, CD8+ cytotoxic T cells and NK cells, as well as skewing of CD4+ and CD8+ T memory cell subset distributionss, suggesting failure of an early anti-myeloma response, which is replaced by progressive immunosuppression, and dysfunction and exhaustion of CD8+ T cell tumor cytotoxicity.

Our new model is a flexible tool to investigate the early cellular interactions that initiate immunosuppression and MM disease progression. The model can also be used to test the efficacy of new therapeutic strategies.

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