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Aug 20, 2023
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Bio based Breakthrough in Immunotherapy

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Scientists at UCLA Jonsson Comprehensive Cancer Center have identified potential new biomarkers that could indicate response to immunotherapy in people diagnosed with metastatic melanoma.

The researchers found that when T cells are activated, they release a protein called CXCL13 that helps attract more B and T cells to the tumor site. The B cells then present specific parts of the tumor to the T cells, which increases the activity of the T cells and enhances their ability to fight the cancer. This collaboration between T cells and B cells was associated with improved survival in patients with metastatic melanoma who received immunotherapy, but not in patients receiving targeted therapies such as MEK inhibitors.

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

“Based on our data, increased B cells and CXCL13 protein in tumors following immunotherapy may be predictive biomarkers of durable immunotherapy response in melanoma patients and may be a pathway to improve response rates to immunotherapy in melanoma patients.” One of the paper’s senior authors, Dr. Willie Hugo, an assistant professor of medicine in dermatology at the UCLA David Geffen School of Medicine and a member of the UCLA Jonsson Comprehensive Cancer Center, said. “For example, the combination of anti-PD1 therapy with CXCL13 or B cell-directed therapy may be a strategy for patients who do not respond to checkpoint immunotherapy alone.”

Background

Immune checkpoint inhibitors, which harness the body’s immune system to better attack cancer cells, have revolutionized the way melanoma patients are treated. People with aggressive cancers are now living longer, healthier lives. Despite the remarkable success of using immune checkpoint inhibitors to treat patients with advanced melanoma, it remains difficult to predict who will benefit from such treatments.

Determining the mechanisms that determine how tumors develop resistance to these therapies, and understanding how to identify patients who do and do not respond to these therapies, is critical to the development of new and improved treatments to help improve response rates to these therapies.

Bio Method

To understand why checkpoint immunotherapy may lead to durable antitumor immune responses in some melanoma patients, and why this may not be the case in patients treated with other FDA-approved targeted therapies, such as mutant BRAF and MEK inhibitors. This response occurs less often, and the UCLA team compared immune responses induced by existing standard-of-care treatments targeting and immunotherapy in patients with metastatic melanoma.

The research team completed a comparative genomics analysis using publicly available RNA-seq profiles of melanoma samples collected before and after the two treatments. They found that responses to immunotherapy, but not targeted therapy, were accompanied by a marked clonal diversity of B cell infiltration. Increased B-cell infiltration after immunotherapy was accompanied by a marked upregulation of the B-cell chemokine CXCL13 by T cells.

Influence

“This study suggests that in patients responding to checkpoint immunotherapy, CXCL13 may play an important role in bringing together T and B cells in the tumor microenvironment, and that this collaboration may be key to an effective antitumor response. Further research is needed to determine whether these pathways can be boosted in non-responders to improve outcomes,” said the paper’s co-senior author Melissa Lechner, MD, PhD, Department of Endocrinology, UCLA David Geffen School of Medicine Assistant Professor and member of the UCLA Jonsson Comprehensive Cancer Center.

These data also support a role for B cells in presenting antigens to T cells in the tumor microenvironment and highlight the potential for using B cell-based cancer vaccines to enhance the effectiveness of immune checkpoint immunotherapy.

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

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