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Early B cell changes predict autoimmunity following combination immune checkpoint blockade.

Rituparna Das¹, Noffar Bar¹, Michelle Ferreira^1,2

¹Department of Medicine.

The Journal of Clinical Investigation

|January 9, 2018

Summary

Combination checkpoint blockade (CCB) alters circulating B cells, increasing a specific subset linked to immune-related adverse events (IRAEs). Early B cell changes may predict IRAE risk in cancer patients receiving CCB therapy.

Keywords:

Cancer immunotherapy Immunology Oncology

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Area of Science:

Immunology
Oncology
Cancer Therapy

Background:

Combination checkpoint blockade (CCB) targeting CTLA4 and PD1 receptors shows promise in cancer treatment.
Immune-related adverse events (IRAEs) are a significant challenge limiting the optimal use of CCB.
Understanding treatment-induced immune changes is crucial for managing CCB toxicity.

Purpose of the Study:

To analyze B cell alterations in melanoma patients undergoing CCB therapy (anti-CTLA4, anti-PD1, or both).
To investigate the relationship between B cell changes and the occurrence and timing of IRAEs.
To identify potential biomarkers for predicting CCB-related toxicities.

Main Methods:

Analysis of circulating B cell populations in melanoma patients before and after CCB treatment.
Flow cytometry to identify B cell subsets (e.g., CD21lo B cells) and PD1 expression.
B cell receptor sequencing to assess clonality.
Single-cell RNA sequencing to analyze B cell activation pathways.

Main Results:

CCB therapy induced a decline in total B cells and an increase in CD21lo B cells and plasmablasts.
CD21lo B cells exhibited higher PD1 expression, increased clonality, and proliferation following CCB.
Early B cell changes, particularly in the CD21lo compartment, correlated with the frequency and timing of IRAEs.
Patients with early B cell alterations experienced higher rates of severe IRAEs.

Conclusions:

CCB therapy significantly alters circulating B cell populations, notably increasing CD21lo B cells.
These B cell changes precede and correlate with the development of IRAEs.
Early detection of B cell changes may identify patients at higher risk for severe IRAEs, suggesting potential for preemptive B cell-targeted interventions to mitigate toxicity.