Researchers uncover potential biomarkers of positive response to
immunotherapy
CXCL13-mediated recruitment of B cells could help predict response to immunotherapy

Date:
June 26, 2023
Source:
University of California - Los Angeles Health Sciences
Summary:
Scientists have identified potential new biomarkers that could
indicate how someone diagnosed with metastatic melanoma will
respond to immunotherapy treatment.


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FULL STORY ========================================================================== Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified potential new biomarkers that could indicate how someone diagnosed with metastatic melanoma will respond to immunotherapy treatment.

The researchers found when T cells are activated, they release a protein
called CXCL13, which helps attract more B cells and T cells to the tumor
site. The B cells then show the T cells specific parts of the tumor,
which leads to increased activation of the T cells and their ability
to fight the cancer. This cooperation between T cells and B cells was associated with improved survival in patients diagnosed with metastatic melanoma who were treated with immunotherapy, but not for those who
received targeted therapy (e.g., MEK inhibitors).

These findings could help guide new strategies to improve the
effectiveness of melanoma cancer treatments.

"Based upon our data, increased presence of B cells and CXCL13 protein in
the tumor after immunotherapy treatment may be predictive biomarkers for durable immunotherapy response in melanoma patients and may be avenues
to enhance the response rate to immunotherapy in patients diagnosed
with melanoma," said co- senior author of the paper Willy Hugo, PhD,
assistant professor of Medicine in the division of Dermatology at the
David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center. "For example, combination of anti-PD1
treatments with CXCL13 or B cell-directed therapies may be strategies
for patients who fail to respond to checkpoint immunotherapy alone."
Immune checkpoint inhibitors, which harness the body's immune system
to better attack cancer cells, have revolutionized the way people with
melanoma are treated. People with aggressive forms of the cancer are now
living longer, healthier lives. Despite the remarkable success of using
immune checkpoint inhibitors to treat people with advanced melanoma,
it is still difficult to predict who will benefit from the therapy.

Identifying mechanisms that determine how tumors can become resistant
to these therapies and understanding how to identify patients who will
and will not respond to them is critical to developing new and improved treatments to help improve the response rate of these therapies.

To understand what may drive durable antitumor immune responses seen
with checkpoint immunotherapy in some melanoma patients, and why such
responses are less often seen in patients treated with other FDA-approved targeted therapies, such as mutant BRAF and MEK inhibitors, the UCLA
team compared the immune responses induced by existing standard care
targeted and immunotherapies for people with metastatic melanoma.

The team completed a comparative genomics analysis using published
RNA-seq profiles of melanoma samples collected before and after either
therapy. They found that response to immunotherapy, but not targeted
therapy, is accompanied with significant infiltration of clonally diverse
B cells. The increase of B cell infiltration in response to immunotherapy
is accompanied by a significant upregulation of B-cell chemotactic factor, CXCL13, by T cells.

"This study suggests that CXCL13 may play an important role in bringing together T and B cells in the tumor microenvironment in patients who
respond to checkpoint immunotherapy, and that this cooperation may
be key to effective anti-tumor responses. Further studies are need to
determine if these pathways can be boosted in non-responders to improve outcomes," said co-senior author of the paper Melissa Lechner, MD, PhD, assistant professor of Medicine in the division of Endocrinology at the
David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center.

These data also support a role for antigen presentation by B cells to
T cells in the tumor microenvironment, and highlight the potential of
using B cell- based cancer vaccines to enhance the effectiveness of
immune checkpoint immunotherapies.

The team now plans to further explore these mechanisms in preclinical
cancer models and test whether antigen presenting B cell and CXCL13 manipulation can improve anti-tumor immune responses in non-responders.

This work was supported in part by grants from the National Cancer
Institute (1R01CA236910) and a grant from Parker Institute for Cancer Immunotherapy.

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========================================================================== Story Source: Materials provided by University_of_California_-_Los_Angeles_Health_Sciences.

Original written by Denise Heady. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Lizhong Ding, Lu Sun, Melissa T. Bu, Yanjun Zhang, Lauren N. Scott,
Robert M. Prins, Maureen A. Su, Melissa G. Lechner, Willy
Hugo. Antigen presentation by clonally diverse CXCR5+ B cells to
CD4 and CD8 T cells is associated with durable response to immune
checkpoint inhibitors.

Frontiers in Immunology, 2023; 14 DOI: 10.3389/fimmu.2023.1176994 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230626164211.htm

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