 have developed a novel biomaterial-based system that induces the formation of tertiary lymphoid-like structures, or TLSs. These immune cell clusters are increasingly linked to improved outcomes and treatment responses in cancer. Results of their study was 

published in the Proceedings of the National Academy of Sciences

TLSs are specialized immune structures that sometimes form within tumors, helping the immune system recognize and attack cancer cells. However, many tumors lack these structures, which can limit the effectiveness of immunotherapy. Understanding how TLSs form and function has been challenging because traditional laboratory models cannot easily reproduce them.

Using an innovative approach, researchers created a biodegradable, injectable hydrogel that slowly releases immune-signaling molecules, including chemokines and cytokines, beneath the skin. These signals attract key immune cells such as T cells and B cells to the injection site, where they self organize into TLS-like structures. When tested in mice, these induced immune clusters supported the activation of tumor-targeting T cells and slowed tumor growth.

Q&A with Rana Falahat, PhD, lead author and research scientist in the 

Why are TLSs such an important focus in cancer immunology right now?

The presence of TLSs is increasingly shown to associate with better patient outcomes and improved responses to immunotherapies, making them a key focus in cancer immunology research today.

What challenges exist in studying TLSs in the lab, and how does your model help overcome those challenges?

The origins and functions of TLSs in antitumor immunity remain poorly understood, mainly because suitable mouse models have been lacking. In this study, we developed a biomaterial-based system that induces TLS-like structures in a controlled way, which can be used both as preclinical models to study how TLSs form and function within tumors and as platforms to explore new therapeutic strategies that harness these structures to boost antitumor immunity.

Can you explain, in simple terms, how your biomaterial system works?

We designed biodegradable materials that release immune-signaling molecules, such as chemokines and cytokines, after being injected under the skin. These signals attract immune cells, like T cells and B cells, to the site, where they begin to organize into structures that resemble TLSs found in tumors, allowing us to study how these structures form and function.

How might this research eventually benefit cancer patients, especially those whose tumors lack TLSs?

Tumors without TLSs often resist immunotherapy. By learning how to trigger TLS formation, we hope to help the immune system better recognize and attack these tumors, improving treatment options for patients who currently have limited responses to immunotherapies.

This study was supported by the National Cancer Institute (P30-CA076292, P50-CA168536), the CJG Fund, Chris Sullivan Fund, V Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation.

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Researchers at Moffitt Cancer Center have developed a biomaterial-based system to induce tertiary lymphoid-like structures (TLSs), which are linked to improved cancer outcomes. TLSs, specialized immune structures within tumors, enhance immune recognition and attack on cancer cells, but are often absent in tumors, limiting immunotherapy effectiveness. The researchers created a biodegradable hydrogel that releases immune-signaling molecules, attracting immune cells to form TLS-like structures. This innovation, tested in mice, supports tumor-targeting T cell activation and tumor growth reduction, potentially improving treatment for patients with TLS-deficient tumors.

Investigators at Moffitt Cancer Center have developed a novel biomaterial-based system that induces the formation of tertiary lymphoid-like structures.

Moffitt Study Reveals Way to Spark Immune Hotspots That Attack Tumors

New Immunotherapy Strategy for Enhancing 

Melanoma Treatment | Image Credit: Maris – stock.adobe.com

 have found a new way to boost cancer immunotherapy by targeting a protein called macrophage receptor with collagenous structure, or MARCO. Their study, published in the 

, shows that blocking MARCO in combination with a type of immunotherapy known as anti-CTLA4 therapy, significantly enhances tumor regression in 

The researchers found that inhibiting MARCO changes the behavior of certain immune cells in the tumor, leading to more immune cells entering the tumor and making the anti-CTLA4 therapy more effective. This new approach could help overcome resistance to current treatments, especially in tumors that usually have few immune cells, known as "cold" tumors.

“Our findings provide strong evidence that targeting MARCO can enhance the effectiveness of existing immunotherapies without requiring macrophage depletion,” said 

 associate center director for Translational Science at Moffitt and lead author of the study. “This discovery paves the way for new combination treatment strategies that could improve outcomes for patients with melanoma and potentially other cancers.”

The study highlights that the combination of an anti-MARCO monoclonal antibody with anti-CTLA4 therapy significantly increases immune cell infiltration, including conventional dendritic cells, a key factor in activating a robust anti-tumor immune response. This effect was not observed when MARCO was targeted alongside anti-PD1 therapy, emphasizing the importance of this approach in boosting anti-CTLA4 treatment.

These findings open new avenues for clinical research, with potential applications in treating patients who do not respond to current immunotherapy options. The study also suggests that incorporating MARCO-targeting strategies into neoadjuvant or adjuvant settings may help reduce cancer recurrence risks by enhancing immune priming within the tumor microenvironment.

This study was supported by the National Cancer Institute (P30-CA076292, 1R01-CA148995, 1R01-CA184845, P50-CA168536), the Cindy and Jon Gruden Fund, Chris Sullivan Fund, V Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Researchers at Moffitt Cancer Center have discovered a method to enhance cancer immunotherapy by targeting the MARCO protein. Blocking MARCO, combined with anti-CTLA4 therapy, significantly improves tumor regression in melanoma. This approach alters immune cell behavior, increasing their presence in tumors and enhancing therapy effectiveness, particularly in "cold" tumors. The study suggests that targeting MARCO can boost existing immunotherapies without macrophage depletion, offering new combination treatment strategies. The findings highlight the potential for MARCO-targeting strategies in reducing cancer recurrence and improving patient outcomes.

Moffitt Cancer Center researchers found a way to boost cancer immunotherapy by targeting a protein called macrophage receptor with collagenous structure.

Moffitt Study Finds New Immunotherapy Strategy for Enhancing Melanoma Treatment

A new Moffitt Cancer Center study has identified a specific immune response that may prevent the spread of breast cancer cells within the body. Published in Cancer Immunology Research, the study shows that activating certain immune cells can stop dormant cancer cells from growing into new tumors.

The researchers discovered that CD4+ Th1 cells, a type of immune cell, play a key role in targeting and eliminating dormant cancer cells. These cells, which can remain hidden in the body, have the potential to cause cancer to return, sometimes years after initial treatment.

“We found that the CD4+ Th1 immune response, especially the cytokine IFN-γ, can force these dormant cells into a state where they can no longer grow or spread,” said Brian Czerniecki, MD, PhD, chair of Moffitt’s Breast Oncology Department and lead author of the study. “This could be a game-changer in preventing cancer recurrence.”

The study also found that blocking cholesterol biosynthesis in these cells helps reduce their ability to survive and spread. Cholesterol plays an important role in cancer cell development, and the Moffitt researchers believe that targeting this pathway with existing drugs could enhance treatment options.

“These findings open the door to new strategies that could be combined with current therapies to stop cancer before it returns,” Czerniecki said.

Researchers also analyzed data from breast cancer patients and found that those with higher levels of CD4+ Th1 cells had a lower risk of cancer recurrence. This suggests that immune-boosting therapies could play a large role in long-term cancer management.

The implications of this study extends beyond breast cancer. Researchers believe the same immune response could be effective against other types of cancer, such as melanoma and lung cancer. By understanding how the immune system naturally targets and suppresses dormant cancer cells, this research could lead to broader applications in oncology, potentially improving survival rates for many patients.

Further studies are needed to determine how this immune response can be enhanced in patients. Future clinical trials will explore whether existing cholesterol-lowering drugs, combined with immunotherapy, can provide long-term protection against cancer recurrence.

This work was supported by the National Cancer Institute (P30CA076292), the Department of Defense (W81XWH-19-1-0675 and W81XWH-16-1-0385), Pennies in Action and a Miles for Moffitt Milestone Award from Moffitt Cancer Center.

A recent study from Moffitt Cancer Center has identified a specific immune response that may prevent breast cancer recurrence by targeting dormant cancer cells. The research highlights the role of CD4+ Th1 cells and the cytokine IFN-γ in inhibiting the growth and spread of these cells. Additionally, blocking cholesterol biosynthesis in cancer cells could enhance treatment efficacy. The findings suggest potential applications for other cancers, such as melanoma and lung cancer, and propose combining cholesterol-lowering drugs with immunotherapy to improve long-term cancer management.

A new Moffitt Cancer Center study has identified a specific immune response that may prevent the spread of breast cancer cells within the body.

Moffitt Study Identifies Immune Response That May Stop Breast Cancer from Spreading

Moffitt Cancer Center researchers have found new insights into how metabolic changes associated with aging can impact immune responses against tumors. Their study, published in Oncogene, explores how increased methylmalonic acid impairs the activation and effector functions of CD8+ T cells, immune cells that play a vital role in fighting cancer.

Methylmalonic acid levels are normally low in healthy individuals. Elevated levels have been linked to aging and vitamin B12 deficiency, raising questions about their role in cancer biology.

“Our research shows that methylmalonic acid not only increases with age but also makes CD8+ T cells weaker by disrupting their energy production,” said Ana Gomes, Ph.D., lead author on the study and principal investigator in the Molecular Oncology Department at Moffitt. “This makes it harder for the immune system to fight cancer, suggesting that targeting methylmalonic acid could help improve cancer treatment.”

Researchers found that methylmalonic acid treatment significantly reduced the activity of CD8+ T cells, an important component of the immune response to tumors. The study’s results indicate that methylmalonic acid influences global gene expression in these cells, leading to the downregulation of key pathways involved in immune activation and metabolism.

The study also highlights the role of methylmalonic acid in skewing the tumor microenvironment, affecting not only T cells but also other immune cells, potentially contributing to a more favorable environment for tumor growth and metastasis.

These findings suggest that strategies aimed at reducing methylmalonic acid levels or counteracting its effects on CD8+ T cells could enhance antitumor immunity, particularly in older patients who are at greater risk for lung cancer.

This study was supported by the National Institutes of Health (P30 CA076292, P30 CA006516, T32 CA233399, P01 CA250984, P01 CA250984, P01 CA120964, R00 CA218686, R00 CA218686‐04S1, DP2AG0776980, R01 CA279023, R21 AG083720), the American Cancer Society (RSG-22-164-01-MM), the Florida Health Department Bankhead-Coley Research Program (24B03), METAvivor, the Florida Breast Cancer Research Foundation and the Phi Beta Psi Sorority.

A study by Moffitt Cancer Center researchers reveals that metabolic changes linked to aging, specifically increased methylmalonic acid, impair CD8+ T cell function, crucial for cancer defense. Elevated methylmalonic acid, associated with aging and vitamin B12 deficiency, disrupts energy production in these cells, weakening immune responses against tumors. The research indicates that methylmalonic acid alters gene expression, affecting immune activation and metabolism, and skews the tumor microenvironment. Targeting methylmalonic acid could enhance antitumor immunity, especially in older patients at higher risk for lung cancer.

A new study has found a surprising link between high levels of methylmalonic acid and the weakening of CD8+ T cells, shedding light on potential pathways through which aging may promote lung cancer progression.

Moffitt Cancer Center

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Moffitt Study Reveals Way to Spark Immune Hotspots That Attack Tumors

Moffitt Study Finds New Immunotherapy Strategy for Enhancing Melanoma Treatment

Moffitt Study Identifies Immune Response That May Stop Breast Cancer from Spreading

Moffitt Study Links Methylmalonic Acid to Weakening of Immune Cells in Lung Cancer