Dr Boiarsky on Tumor-Associated Macrophages in Metastatic NSCLC

“We saw that in the tumor compartment, increased expression of CD24 was associated with worse progression-free survival, validating the signal that we initially found.”

Daniel Boiarsky, MD, a hematology/oncology fellow at Yale New Haven Hospital, discussed findings from a study of tumor-associated macrophages (TAMs) in patients with metastatic non-small cell lung cancer (NSCLC).

Boiarsky and his coauthors sought to identify molecular features associated with durable responses to anti–PD-1 therapy by comparing gene expression profiles across three patient groups, he began. As expected, long-term responders demonstrated increased expression of interferon-gamma–related genes, PD-L1, and T-cell markers, consistent with an active immune microenvironment, he noted. However, the analysis also revealed an unexpected association between long-term response and increased expression of several TAM genes, including CD206 and CD163, he explained. These markers are typically associated with immunosuppressive macrophage populations, making their association with durable treatment response particularly notable, he said.

Conversely, investigators observed increased expression of CD24 in patients who experienced disease progression, Boiarsky said. CD24 is an antiphagocytic marker expressed by tumor cells and is thought to interact with SIGLEC-10 on macrophages, potentially inhibiting macrophage-mediated phagocytosis, he explained. These findings led Boiarsky and his coauthors to hypothesize that macrophages may play an important role in mediating durable antitumor immunity, while tumor-cell expression of CD24 could interfere with this activity, he added.

Boiarsky and his coauthors subsequently sought to validate these findings using external patient cohorts and higher-resolution spatial profiling techniques. In a Yale cohort of 47 patients with metastatic NSCLC treated with anti–PD-1 therapy, either alone or in combination with chemotherapy, pretreatment tumor biopsies were analyzed using multiplex immunofluorescence, he explained. Patients who experienced long-term responses, defined as progression-free survival exceeding 3 years, demonstrated a higher density of CD14-positive macrophages, particularly in close proximity to tumor cells, he said.

Additional analyses were conducted to validate the CD24 findings using two external cohorts, Boiarsky said. The Yale cohort was evaluated using spatial transcriptomics, while a separate cohort from the University of Queensland included 26 patients, he said. Across these analyses, increased CD24 expression within the tumor compartment was associated with worse progression-free survival, supporting the initial observation, he concluded.