Unlocking the Mysteries of TIL Therapy Resistance in Advanced Lung Cancer
In a groundbreaking study published in Nature Cancer, researchers from the Moffitt Cancer Center have illuminated critical barriers that hinder the efficacy of tumor-infiltrating lymphocyte (TIL) therapy in treating metastatic non-small cell lung cancer (NSCLC). This pioneering work offers fresh insights into why some patients fail to respond to this promising immunotherapy and opens new avenues for refining treatment strategies.
TIL therapy, an avant-garde form of cellular immunotherapy, harnesses the body’s own immune cells to combat cancer. The process involves surgically excising a patient’s tumor, from which highly potent immune cells called lymphocytes are isolated. These TILs, having naturally infiltrated the tumor site, are expanded ex vivo to tremendous numbers before being reintroduced into the patient’s bloodstream to intensify the anti-cancer immune response. Although this treatment has delivered remarkable clinical responses in several cancers, its success in NSCLC has been inconsistent.
The Moffitt research team meticulously analyzed tumor and immune cell samples from a cohort of NSCLC patients previously enrolled in a TIL therapy clinical trial. Their comparative approach involved distinguishing biological differences between those who exhibited favorable responses and those who did not. A key observation was that in non-responders, the infused TILs failed to persist or remain functionally active over time. This lack of sustained T cell survival undermines the therapeutic impact, effectively allowing the cancer to regain a foothold.
Beyond T cell persistence, the investigation uncovered phenomena related to tumor antigen dynamics. Tumor antigens are molecular flags present on cancer cells that enable immune cells to recognize and target malignancies. Surprisingly, in patients unresponsive to TIL therapy, certain neoantigens—the mutated proteins that are pivotal for immune recognition—showed a marked decline or even complete loss as treatment progressed. This antigenic attrition presents a formidable evasion mechanism by the tumor, granting it stealth against immune detection and attack.
Dr. Chao Wang, Ph.D., a clinical science researcher at Moffitt and co-author of the study, elaborated on these findings by emphasizing the multifactorial nature of resistance: “Our in-depth exploration has revealed that both the temporal depletion of effective T cells and the tumor’s ability to shed critical antigens converge to thwart TIL therapy efficacy. These dual challenges must be addressed to push the boundaries of therapeutic success.”
Subsequent analyses highlighted that patients durable to therapy maintained a pool of TILs capable of surviving and proliferating within the host environment, thereby continuously exerting anti-tumor activity. In contrast, non-responders demonstrated rapid decline in T cell viability and function post-infusion, which correlated closely with disease progression. The loss of immunologically targetable neoantigens further exacerbated this failure, suggesting that tumor evolution under immune pressure leads to a form of adaptive resistance.
From these insights, experts like Dr. Ben Creelan, M.D., a medical oncologist at Moffitt’s Thoracic Oncology Department and co-author, emphasized the imperative to innovate therapeutic approaches. “Enhancing the longevity and functional fitness of T cells post-infusion, alongside strategies to stabilize or reintroduce key tumor antigens, may be the linchpin for improving patient outcomes,” he noted. The future may well involve integrating gene-editing technologies to engineer more robust TILs that resist exhaustion and evade tumor-induced suppression.
Moreover, the potential to manipulate tumor antigenic landscapes opens exciting prospects. Gene-editing or molecular interventions could restore or mimic lost neoantigens, preventing tumors from escaping immune surveillance. By maintaining a consistent portfolio of recognizable targets, TIL therapies could sustain their cytotoxic activity, leading to more durable clinical remissions.
To accelerate progress in this domain, the Moffitt team has made their sequencing data and research materials publicly accessible via National Institutes of Health archives. This act of scientific generosity is aimed at fostering global collaboration, enabling other researchers to build upon their findings and explore combinatorial treatment modalities that could overcome identified resistance mechanisms.
The implications of this study are profound, highlighting the dynamic interplay between immune cell persistence and tumor evolutionary strategies. It underscores the need for a holistic approach in immunotherapy development—one that simultaneously addresses T cell survival, antigen stability, and tumor microenvironment modulation. These insights could steer future clinical trial designs toward combination therapies pairing TIL infusion with agents that bolster immune cell metabolism or restore antigen expression.
As TIL therapy continues to mature, integrating advances such as next-generation sequencing, single-cell profiling, and molecular engineering will be paramount. This multi-angled approach ensures that personalized immunotherapy regimens become increasingly precise, tailored not just to tumor type but to the individual’s tumor and immune system dynamics over the course of treatment.
Ultimately, overcoming the dual hurdles of T cell attrition and neoantigen loss could transform TIL therapy from a niche treatment into a frontline weapon in the fight against metastatic NSCLC. This breakthrough represents a pivotal step toward turning what has been experimental promise into widespread clinical reality, potentially changing the prognosis for thousands of lung cancer patients worldwide.
The Moffitt Cancer Center stands at the forefront of this evolving frontier, combining immunological expertise with translational research to push the boundaries of cancer therapy. By continuing to dissect the underlying biology of immune resistance, researchers aspire to develop next-generation therapies that deliver sustained remission and improved quality of life for patients battling advanced lung cancer.
Subject of Research: People
Article Title: Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy
News Publication Date: 8-May-2025
Web References:
- Moffitt Cancer Center: https://moffitt.org/
- Nature Cancer Article DOI: http://dx.doi.org/10.1038/s43018-025-00946-x
- TIL Therapy Overview at Moffitt: https://www.moffitt.org/treatments/immunotherapy/til-therapy/
References:
Wang C., Creelan B., et al. (2025). Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy. Nature Cancer. DOI: 10.1038/s43018-025-00946-x
Keywords: Immunotherapy, Tumor-Infiltrating Lymphocytes, Lung Cancer, Non-Small Cell Lung Cancer, T Cell Persistence, Neoantigen Loss, Tumor Immune Evasion, Cellular Immunotherapy, Cancer Resistance Mechanisms
