Hyperinflammation in Hematologic Malignancies: From Bedside to Bench and Back

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Adi Zoref-Lorenz, MD, PhD1,2,3

1Hematology Institute, Meir Medical Center, Kfar Saba, Israel

2Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel

3Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

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Hemophagocytic lymphohistiocytosis (HLH) is a deadly hyperinflammatory syndrome most recognized in infants with familial HLH (FHL), where mutations in the perforin pathway cause cytotoxic T-cells to become hyperactive yet ineffective. The resulting interferon‑γ storm fuels relentless macrophage activation, leading to pancytopenia, organ failure, and often death. In adults, HLH most often emerges in the context of hematologic malignancies (HMs), a setting where there are no germline defects to explain the phenomenon. The underlying biology is largely unknown, but the clinical impact is substantial, with patients facing a 5-year survival rate of just 10–20%.

 

In a multi-center study, we developed the Optimized HLH Inflammatory (OHI) Index, a simple serum-based tool that utilizes soluble CD25 and ferritin to identify a subgroup of cancer patients who do not die of their malignancy per se, but rather from an inflammatory spiral leading to multi-organ failure. Building on this, deep proteomic profiling — analyzing more than 7,000 proteins in patient sera — revealed that the hyperinflammatory “fingerprint” of HM‑OHI⁺ patients mirrors that of children with familial HLH. We observed the same signature of overactivated cytotoxic T cells, interferon–γ–driven cytokine signaling, complement activation, and innate immune response, which we later validated using an orthogonal method in an independent cohort. Although T-cell suppression is lifesaving in FHL, applying the same strategy in cancer could deplete the T-cells essential for tumor surveillance and lead to inferior cancer outcomes. Our early findings suggest that cytotoxic T-cells heavily infiltrate these patients’ tumors, yet their inability to kill the tumor cells remains an enigma.

 

Our work in the Oncologic HyperInflammation (OHI) Laboratory demonstrates that the OHI index identifies a misdirected immune program in 10-30% of patients with blood cancer. By mapping inflammatory pathways and tumor–immune crosstalk, we aim to develop therapies that reduce harmful inflammation while preserving anti-cancer immunity.