BCRF investigator Dr. Xiang Zhang and his colleagues are examining the crosstalk between a breast tumor and the body’s immune system to understand why some cancers do not respond to treatment.
He and his team recently published results in Nature Cell Biology showing that they’d identified two specific immune cell abnormalities that may serve as blood biomarkers to determine whether patients with triple-negative breast cancer (TNBC) will respond to chemotherapy and immunotherapy.
Below, read more about these findings and what they mean for patients.
TNBC is so named for the fact that it lacks the three key targets for current treatments: estrogen and progesterone receptors and high levels of the HER2 protein. As such, this form of breast cancer can be difficult to treat. Recently, there have been significant advances in immunotherapy for treating TNBC but only about 15 to 20 percent of patients benefit.
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One reason for this lack of efficacy is that tumors, including breast tumors, have been shown to influence their microenvironment to evade the body’s main defence: the immune system. This allows them to grow and spread uncontrollably. There are also other tumor-induced changes that occur because of how the body responds to the cancer. Dr. Zhang’s group was interested in finding out more about how certain TNBC tumors manipulate their surrounding environment and make immunotherapy ineffective.
Although most people have heard of the immune system, its components and complexicity are relatively unknown. For example, the lymphatic system is part of the immune system. It’s composed of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lymphatic tissue and lymph, the clear fluid carried by the vessels back to the heart for re-circulation. In addition, there are several types of immune cells that are activated in response to perceived foreign factors in the body.
The immature form of immune cells—for example, myeloid, neutrophil, and B cells—originate from the bone marrow and migrate to other organs of the lymphatic system for further maturation. In prior work, Dr. Zhang’s team found that B cell development in the bone marrow is crucial for ensuring that effective B cells form. However, some tumors can block B cell development, thereby blunting an immune response and promoting therapeutic resistance. Without this effect, B cells can aggregate in tumors, which correlates with better prognosis and clinical outcomes from immunotherapy. Dr. Zhang is investigating these observations and specifically how B cell development is influenced by the presence of TNBC tumors and their role in tumor immunosuppression.
“Previous studies highlighted T cells as the major fighters of breast cancer. The role of B cells, another major population of adaptive immune cells, remains less understood,” Dr. Zhang said.
Building on previous findings, Zhang’s team examined changes in B cells from patient blood samples and identified three distinct subgroups of tumor-induced B cell abnormality (TiBA). The first group (TiBA 0) shows no characteristic difference compared to the normal B cell population. TiBA 1 exhibits a global reduction in B cells, presumably due to competition with immature myeloid cells in the bone marrow. TiBA 2 results in an accumulation of immature B cells, which is likely due to an excessive number of neutrophils preventing the B cells from maturing.
In further studies, the team found that B cell changes in both TiBA 1 and TiBA 2 types lead to an immunosuppressive effect and poorer response to treatment. In a study of 35 patients with TNBC, 78.6 percent of TiBA 0 patients had a complete response to treatment with chemotherapy and immunotherapy, while only 33.3 percent of TiBA 1 and TiBA 2 patients had a complete response.
Their results also indicate that the interaction between myeloid, neutrophil, and immature B cells at the bone marrow level may determine the differences between TiBA 1 and TiBA 2, suggesting that immune-suppressive mechanisms go beyond the local tumor environment. Dr. Zhang’s work provides support for tracking early B and myeloid cells to potentially reveal differences in TiBA and B cell dysfunction in a patient’s bone marrow.
Dr. Zhang’s team has shown that tumor-induced changes are complex within TNBC, as the same immune cells can be systemically altered in divergent directions to become effective or immunosuppressive. Looking ahead, the team will continue to conduct comprehensive molecular characterization to determine how B cells can be used as indicators of immune system status and biomarkers to predict therapeutic outcomes. They also hope to identify molecular targets that can be leveraged to improve therapies that rely on a functional immune system.
This study reveals the potential of using early immune cell profiles as biomarkers to quantify dysfunctional immune cells in a patient’s blood and bone marrow. For patients, particularly those with TNBC, these profiles could predict their immune system status and how they might respond to therapy. Further studies are needed to determine the feasibility of clinical assays that are sensitive enough to inform treatment decisions and bring precision immuno-oncology into the clinic.
“With this new information, we can design novel blood assays to identify patients who may benefit from current therapies and who will need additional treatments to overcome the potential resistance,” Dr. Zhang said. “This work is supported almost exclusively by funding from BCRF, and we are genuinely grateful.”
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