Title: Pretreatment Immune Profiles Linked to Immune-Related Adverse Events May Guide Personalized Management Strategies

Scientists have identified specific blood markers that may help predict which cancer patients undergoing immunotherapy are at higher risk for developing serious side effects, according to research published in a recent study.

The study analyzed pretreatment blood samples from 51 patients with metastatic renal cell carcinoma receiving a combination of nivolumab and ipilimumab, two immunotherapy drugs known as immune checkpoint inhibitors. Researchers found that higher levels of lymphocytes and monocytes in the blood before treatment were strongly associated with an increased likelihood of experiencing immune-related adverse events (irAEs).

Higher lymphocyte and monocyte counts (odds ratios [ORs] 14.36 and 9.90, respectively) were significantly associated with an increased risk of irAEs, whereas higher neutrophil counts and C-reactive protein levels (ORs 0.08 and 0.27, respectively) were associated with a decreased risk.

Study abstract

Conversely, elevated neutrophil counts and C-reactive protein levels were linked to a lower risk of developing these adverse events. To further understand the biological mechanisms, researchers conducted whole-blood transcriptomic analyses, which revealed increased activity in pathways related to lymphocyte and humoral immunity, while pathways tied to neutrophil function and inflammation were downregulated in patients who later experienced irAEs.

Using computational cell sorting techniques, the study also showed a reduction in neutrophil fractions and an increase in CD8⁺ T cells and activated memory CD4⁺ T cells among those who developed side effects, indicating an immune profile dominated by adaptive rather than innate responses.

An exploratory analysis pinpointed five genes—ANAPC1, CDK4, MCM6, GRAP2, and BST2—as potential contributors to the immune characteristics associated with irAE development. These findings suggest that pretreatment immune profiling could one day support personalized approaches to managing immunotherapy toxicity, allowing for closer monitoring or early intervention in high-risk patients.

Immune-related adverse effects remain a significant challenge in cancer immunotherapy, as these treatments can trigger inflammation in healthy organs, mimicking autoimmune diseases and ranging from mild rashes to life-threatening colitis or hepatitis. Early detection and management are crucial to maintaining the balance between treatment effectiveness and patient safety.

While the study focused on kidney cancer patients, the insights may have broader implications for improving the safety of immunotherapies across other cancer types. Researchers emphasize that validating these biomarkers in larger, more diverse cohorts will be essential before they can be routinely used in clinical decision-making.