Characterization of Immune Infiltrates Associated with Radiation Necrosis in the Setting of Brain Metastases Following Stereotactic Radiosurgery and Immunotherapy

Abstract

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) represents an inflammatory sequel and hyalinization secondary to radiotherapy (RT). The impact of immunotherapy on immune cellular microenvironment in patients with brain metastasis (BM) is unknown. The objective of this study was to characterize the inflammatory microenvironment in the setting of RN compared to recurrent tumor and determine whether immunotherapy treatment affects cellular infiltrates. <h3>Materials/Methods</h3> Adult patients with BM from solid tumors who received both systemic immunotherapy (IO) and radiotherapy (RT) who then underwent resection for progressively enlarging abnormality following IO+RT were retrospectively analyzed. A group of BM patients who developed RN confirmed by surgery and who did not receive IO was reviewed as control. Surgical specimens were stained for immune and inflammatory components and reviewed by a neuro-pathologist who remained blinded during the analysis. The presence or absence of lymphocytes, cuffing, plasma cells, macrophages, and fibrinoid were used as surrogates of immune infiltrate and were characterized in a semiquantitative manner. <h3>Results</h3> A total of 18 patients were categorized into 1 of 3 groups: (1) Necrosis, IO+RT (2) Tumor, IO+RT (3) Necrosis, RT. The median age was 61.5 years (range 37-82 years). 77% of primary cancers were melanoma. Review of surgical specimens demonstrated a higher but not statistically significant extent of immune infiltrates in the groups with RN when compared to the group with tumor recurrence. Higher lymphocytes, cuffing, and macrophages were found in "Necrosis, IO+RT" patients compared to "Tumor, IO+RT" patients (83.3% and 16.7%, respectively). Further analysis demonstrated 100% of "Necrosis, IO+RT" patients have quantifiable cell counts while 83.3% of "Tumor, IO+RT" patients do not have quantifiable cell counts. <h3>Conclusion</h3> The immune microenvironment of BM following radiotherapy and immunotherapy shows higher levels of cell infiltrates in the RN setting versus recurrent tumor setting. Lower level of presence of immune cells in tumor recurrence following IO+RT may suggest an environment lacking primed immune cells with implication to potential decreased efficacy in immunotherapy.