Teaching the Immune System to Fight Lung Cancer

Authored by: Abigail Chang

Art by: Joshua Choi

Lung cancer remains the leading cause of cancer-related death worldwide. While its rapid growth contributes to its severity, an equally important factor is its ability to evade the immune system. Rather than escaping detection by chance, lung tumors actively suppress immune responses that would normally identify and destroy them. This ability to “turn off” the immune system allows cancer to persist and spread. As a result, understanding and reversing immune suppression has become a central goal in modern oncology. One promising strategy is neoadjuvant immunotherapy, which involves using immune checkpoint inhibitors before surgical tumor removal. By intervening early, this approach aims not only to shrink tumors but also to retrain the immune system to recognize and fight cancer over the long term.

Immune Suppression in Lung Cancer

Under normal conditions, the immune system plays a critical role in detecting abnormal cells. CD8⁺ T cells, in particular, are responsible for recognizing and killing cancerous cells by identifying unusual proteins, or antigens, on their surface. Lung cancer, however, can often disrupt this process.

A key mechanism of “immune evasion” involves the interaction between two molecules: PD-1, found on T cells, and PD-L1, expressed by many tumor cells. When PD-L1 binds to PD-1, it sends an inhibitory signal that reduces T cell activity. This signal limits the ability of T cells to multiply, produce signaling molecules, and carry out their cytotoxic functions, effectively shutting down the immune response [1]. Over time, repeated exposure to tumor antigens can push T cells into a state known as exhaustion, in which they become less effective at responding to threats. This exhausted state is reinforced by long-lasting changes in gene regulation, including modifications that increase PD-1 expression and maintain immune suppression [2].

To overcome this, researchers have developed immune checkpoint inhibitors, a class of drugs designed to block these inhibitory signals. Nivolumab (Opdivo) is one such therapy that targets the PD-1 receptor. By binding to PD-1, it prevents interaction with PD-L1 and restores T cell activity [3]. Once reactivated, T cells can expand in number and regain their ability to kill tumor cells. Interestingly, tumors with a high number of genetic mutations tend to respond better to this treatment, likely because they produce more abnormal proteins that the immune system can recognize [4]. Clinical evidence supports the effectiveness of this approach. In patients with advanced non-small cell lung cancer, nivolumab has been shown to improve overall survival compared to traditional chemotherapy. Long-term follow-up studies demonstrate that some patients experience durable responses, remaining alive for years after treatment begins [5]. These findings highlight the potential of immunotherapy to produce lasting benefits.

Rationale for Neoadjuvant Treatment

While immunotherapy has shown success in advanced disease, there is growing interest in using it earlier in treatment. Neoadjuvant immunotherapy, given before surgery, offers several important advantages. When the tumor is still present, it serves as a rich source of antigens, allowing the immune system to mount a broader and more effective response. This exposure helps generate T cells that are specifically trained to recognize the tumor.

Importantly, these activated T cells can persist even after the tumor is surgically removed. This creates a form of immune memory that enables the body to detect and eliminate any remaining cancer cells, including those that may have spread but are too small to detect. In this way, immunotherapy complements surgery by addressing disease that cannot be seen through imaging or pathology. The success of neoadjuvant treatment is often measured using major pathological response (MPS), defined as 10 percent or less viable tumor remaining after therapy. This measure has emerged as a strong predictor of long-term survival in lung cancer patients [6]. Studies have shown that neoadjuvant PD-1 blockade significantly increases rates of major pathological response compared to traditional approaches [7].

Compared to chemotherapy, immunotherapy also offers a different side effect profile. Chemotherapy targets rapidly dividing cells, which can lead to damage in healthy tissues such as bone marrow, the digestive tract, and hair follicles. This results in well-known side effects like fatigue, nausea, and hair loss. In contrast, checkpoint inhibitors work by enhancing the body’s natural immune response rather than directly killing cells. As a result, patients often experience fewer severe side effects (adverse effects). However, because these therapies activate the immune system, they can sometimes cause immune-related side effects that require careful monitoring and management [5].

Future Directions

Despite its promise, immunotherapy is not effective for all patients. Some tumors are resistant from the outset, while others develop resistance over time. In addition, immune-related side effects remain an important consideration. Ongoing research is focused on identifying biomarkers that can predict which patients are most likely to benefit, optimizing treatment timing and duration, and developing combination therapies that improve outcomes.

Ultimately, the goal is to create personalized immunotherapy treatment regimes that maximize effectiveness while minimizing adverse effects (AEs). Neoadjuvant immunotherapy represents a critical step toward this vision by integrating immune-based treatment into earlier stages of disease. Already, immunotherapy has transformed cancer care, shifting the focus towards training the immune system as a central component of treatment. 

Works Cited: 

1. Topalian, S. L., et al. (2012). Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New England Journal of Medicine, 366(26), 2443–2454. https://doi.org/10.1056/NEJMoa1200690

2. Youngblood, B., et al. (2011). Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8⁺ T cells. Immunity, 35(3), 400–412. https://doi.org/10.1016/j.immuni.2011.06.015

3. Chen, D., et al. (2019). The FG loop of PD-1 serves as a hotspot for therapeutic monoclonal antibodies. iScience, 14, 113–124. https://doi.org/10.1016/j.isci.2019.03.011

4. Rizvi, N. A., et al. (2015). Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 348(6230), 124–128. https://doi.org/10.1126/science.aaa1348

5. Borghaei, H., et al. (2021). Five-year outcomes from CheckMate 017 and CheckMate 057: Nivolumab versus docetaxel in previously treated non-small cell lung cancer. Journal of Clinical Oncology, 39(7), 723–733. https://doi.org/10.1200/JCO.20.01605

6. Hellmann, M. D., et al. (2018). Pathological response as a surrogate endpoint in neoadjuvant trials of non-small cell lung cancer. Journal of Thoracic Oncology, 13(1), S8–S9. https://doi.org/10.1016/j.jtho.2017.11.007

7. Forde, P. M., et al. (2018). Neoadjuvant PD-1 blockade in resectable lung cancer. New England Journal of Medicine, 378(21), 1976–1986. https://doi.org/10.1056/NEJMoa1716078