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Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

ABSTRACT: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients.

SUBMITTER: Wang HC

PROVIDER: S-EPMC8497102 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. METHODS:We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS:The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0-94.6) than intratumoral macrophages (27.5%; 95% CI: 0-81.1, p?=?0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p?=?0.0429), with very low coefficient correlation (??=?0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p?=?0.0008; better MSKCC score, p?=?0.0103; peritumoral macrophages: low proportion of LDH elevation, p?=?0.0064) and longer OS (for intratumoral macrophages: high PD-L1?=?60?months, 95% CI?=?30-132.6; low PD-L1?=?24?months, 95% CI?=?11-48; p?=?0.032; for peritumoral macrophages: high PD-L1?=?60?months, 95% CI?=?30.7-NR; low PD-L1?=?14?months, 95% CI?=?3-26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR?=?0.30, 95% CI?=?0.12-0.77, p?=?0.0129). CONCLUSIONS:Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

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Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

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