Findings

Scientists on the UCLA Jonsson Comprehensive Cancer Center have identified potential latest biomarkers that might indicate how someone diagnosed with metastatic melanoma will reply 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 ends up in increased activation of the T cells and their ability to fight the cancer. This cooperation between T cells and B cells was related to improved survival in patients diagnosed with metastatic melanoma who were treated with immunotherapy, but not for many who received targeted therapy (e.g., MEK inhibitors).

These findings could help guide latest strategies to enhance the effectiveness of melanoma cancer treatments.

Based upon our data, increased presence of B cells and CXCL13 protein within the tumor after immunotherapy treatment could also be predictive biomarkers for durable immunotherapy response in melanoma patients and will be avenues to boost the response rate to immunotherapy in patients diagnosed with melanoma. For instance, combination of anti-PD1 treatments with CXCL13 or B cell-directed therapies could also be strategies for patients who fail to answer checkpoint immunotherapy alone.”

Willy Hugo, PhD, co-senior writer of the paper, assistant professor of Medicine within the division of Dermatology on the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center

Background

Immune checkpoint inhibitors, which harness the body’s immune system to raised attack cancer cells, have revolutionized the best way individuals with melanoma are treated. Individuals with aggressive types of the cancer are actually living longer, healthier lives. Despite the remarkable success of using immune checkpoint inhibitors to treat individuals with advanced melanoma, it remains to be difficult to predict who will profit from the therapy.

Identifying mechanisms that determine how tumors can turn into immune to these therapies and understanding find out how to discover patients who will and is not going to reply to them is critical to developing latest and improved treatments to assist improve the response rate of those therapies.

Method

To grasp 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, comparable to mutant BRAF and MEK inhibitors, the UCLA team compared the immune responses induced by existing standard care targeted and immunotherapies for individuals with metastatic melanoma.

The team accomplished a comparative genomics evaluation 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 rise of B cell infiltration in response to immunotherapy is accompanied by a major upregulation of B-cell chemotactic factor, CXCL13, by T cells.

Impact

“This study suggests that CXCL13 may play a vital role in bringing together T and B cells within the tumor microenvironment in patients who reply to checkpoint immunotherapy, and that this cooperation could also be key to effective anti-tumor responses. Further studies are need to find out if these pathways could be boosted in non-responders to enhance outcomes,” said co-senior writer of the paper Melissa Lechner, MD, PhD, assistant professor of Medicine within the division of Endocrinology on the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center.

These data also support a task for antigen presentation by B cells to T cells within the tumor microenvironment, and highlight the potential of using B cell-based cancer vaccines to boost 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.

Journal

The study was published within the journal Frontiers in Immunology.

Authors

The study’s other senior writer is Dr. Melissa Lechner, assistant professor of Medicine within the division of Endocrinology, Diabetes. The study’s first writer is Lizhong Ding. Other UCLA authors include Lu Sun, Melissa Bu, Yanjun Zhang, Lauren Scott, Robert Prins and Maureen Su.

Funding

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

Source:

University of California – Los Angeles Health Sciences

Journal reference:

Ding, L., et al. (2023) Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is related to durable response to immune checkpoint inhibitors. Frontiers in Immunology. doi.org/10.3389/fimmu.2023.1176994.