Early T Cell Changes in Cancer Immunotherapy Patients Tied to Severe Immune Side Effects

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMOct 25 2024

Immune-related side effects or adverse reactions (irAEs) can cause serious health issues in cancer patients undergoing immunotherapy involving immune checkpoint inhibitors.

In a recent study published in the Journal of Clinical Investigation, researchers analyzed cytokines and immune cells from blood samples collected from cancer patients with solid tumors to explore the biological mechanisms underlying the adverse reactions to immune checkpoint inhibitors. The insights gained from the study could help improve treatment strategies and reduce the risk of irAEs.

​​​​​​​Study: Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures. Image Credit: Tati9/Shutterstock.com

Background

Immune checkpoint inhibitors are a highly effective method for cancer treatment but can cause serious adverse reactions that affect various organs.

Although immune checkpoint inhibitors boost the immune system’s ability to fight tumors, they also disrupt the body’s ability to tolerate its tissue, leading to various autoimmune reactions and adverse effects.

Furthermore, the tradeoff between treatment benefits and adverse reactions is complex, and many patients often experience side effects without benefiting from the therapy.

Additionally, efficient methods to understand the underlying factors and predict who will develop irAEs are lacking, presenting substantial challenges in the management of adverse reactions to immunotherapy.

About the Study

In the present study, the researchers aimed to better understand the immune mechanisms behind irAEs by analyzing the specific proteins, such as cytokines and immune cells, in a diverse group of cancer patients.

The study population also included patients with autoimmune diseases, as well as Black patients, who are often underrepresented in clinical trials for immune checkpoint inhibitors.

The goal of the study was to identify biological markers that were effective in the early prediction of the patient developing irAEs, which can help build better adverse reaction management and prevention strategies to ensure that the patients receive the benefits of immune checkpoint inhibitors with as few risks to their health as possible.

The researchers included both males and females, and sex was considered as a variable in the statistical models used for the analysis. Blood samples were collected from the patients at baseline before the treatment was initiated and then during the first two months of immune checkpoint inhibition therapy.

Furthermore, the researchers ensured that the blood samples were collected within a month of irAEs onset and before immunosuppressive medications that could impact the cytokine levels were administered.

The blood samples were used to analyze the cytokine levels and immune cells that could help predict irAEs.

The blood sample analysis results of patients who developed irAEs after the administration of immune checkpoint inhibitors were compared with those of patients who did not develop any adverse reactions after the treatment.

Additionally, time-to-event analyses were conducted to predict irAEs. This method evaluated how long it took for irAEs to develop and how the cytokines and immune cells changed over time after the administration of immune checkpoint inhibitors.

Fold changes in the cytokine levels were calculated relative to the baseline to account for variability among the patients.

The study applied Cox proportional-hazard models to estimate the risk of irAEs and survival probabilities while adjusting for multiple factors. The likelihood of irAE onset and survival outcomes were also estimated.

Major Findings

The study found that specific immune responses involving cytokines and immune cells were strongly associated with the development of irAEs in cancer patients after the administration of immune checkpoint inhibitors.

Specifically, the study found an early increase in interleukin (IL)-6, IL-5, IL17f produced by T helper 17 (Th17) cells, IL-13 produced by T helper 2 (Th2) cells, and tumor necrosis factor-alpha (TNF-α), which was linked to a higher risk of developing equal to or greater than grade 2 adverse reactions to immune checkpoint inhibitors.

Among the interleukins, IL-17f and IL-6 showed the strongest associations with irAEs to immune checkpoint inhibitors. Furthermore, the presence of Th17 cells and the expansion of Th2 cells in the early stages of treatment were also associated with irAEs.

The overlap of IL-3, IL-5, and IL-23 between irAEs and allergic reactions such as dermatitis and asthma and the role of Th17 in driving inflammation in autoimmune diseases indicated that irAEs could share common underlying mechanisms with these conditions.

The cytokine patterns also varied with the type of irAE. Adverse reactions such as thyroiditis and colitis were associated with higher levels of IL-17 and IL-6, while inflammatory arthritis showed associations with higher levels of TNF-α.

These findings also indicated that existing medications for autoimmune diseases that could target IL-17, IL-6, and TNF-α could potentially be used to treat irAEs.

Conclusions

Overall, the findings revealed that an increase in the levels of IL-17f, IL-6, and TNF-α in the early stages of immune checkpoint inhibitor therapy for cancer patients was an indicator of a high risk of developing adverse reactions.

Furthermore, the early expansion of Th2 cells and increase in Th17 cells during immunotherapy could serve as potential biomarkers for predicting irAEs.

These findings also highlighted the possible use of autoimmune disease medications targeting these cytokines for the management of irAEs.