Progression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration

Abstract

PURPOSE Understanding the immunobiology of the 15% to 30% of patients with follicular lymphoma (FL) who experience progression of disease within 24 months (POD24) remains a priority. Solid tumors with low levels of intratumoral immune infiltration have inferior outcomes. It is unknown whether a similar relationship exists between POD24 in FL. PATIENTS AND METHODS Digital gene expression using a custom code set—five immune effector, six immune checkpoint, one macrophage molecules—was applied to a discovery cohort of patients with early- and advanced-stage FL (n = 132). T-cell receptor repertoire analysis, flow cytometry, multispectral immunofluorescence, and next-generation sequencing were performed. The immune infiltration profile was validated in two independent cohorts of patients with advanced-stage FL requiring systemic treatment (n = 138, rituximab plus cyclophosphamide, vincristine, prednisone; n = 45, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), with the latter selected to permit comparison of patients experiencing a POD24 event with those having no progression at 5 years or more. RESULTS Immune molecules showed distinct clustering, characterized by either high or low expression regardless of categorization as an immune effector, immune checkpoint, or macrophage molecule. Low programmed death-ligand 2 (PD-L2) was the most sensitive/specific marker to segregate patients with adverse outcomes; therefore, PD-L2 expression was chosen to distinguish immune infiltrationHI (ie, high PD-L2) FL biopsies from immune infiltrationLO (ie, low PD-L2) tumors. Immune infiltrationHI tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. Of note, the immune infiltrationLO subset of patients with FL was enriched for POD24 events (odds ratio [OR], 4.32; c-statistic, 0.81; P = .001), validated in the independent cohorts (rituximab plus cyclophosphamide, vincristine, prednisone: OR, 2.95; c-statistic, 0.75; P = .011; and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: OR, 7.09; c-statistic, 0.88; P = .011). Mutations were equally proportioned across tissues, which indicated that degree of immune infiltration is capturing aspects of FL biology distinct from its mutational profile. CONCLUSION Assessment of immune-infiltration by PD-L2 expression is a promising tool with which to help identify patients who are at risk for POD24.

Tumour‐immune microenvironment in duodenal‐type follicular lymphoma

“…In this regard, several studies have shown that FL patients with high levels of immune infiltration in tumoural tissues have a better response to chemoimmunotherapy compared with those with low immune infiltration. 24,25 Similarly, recent studies showed that CCL20 was overexpressed in DTFL compared with in nFL, 23,26 which is a strong chemotactic factor for lymphocytes; however, its role in the anti-tumour reactions in DTFL remains unknown. In addition, although it was not discussed in this report, 23 the expression of CCL21, a chemoattractant for various leukocytes, was significantly lower in DTFL than in nFL.…”

“…CD8 + TILs play a central role in anti-tumour immunity by imposing selective pressure on malignant cells. 4,25 Several studies have shown that the increased number of CD8 + TILs in the neoplastic follicles was significantly associated with indolent clinical behaviour and favourable clinical outcomes. 5,29,30 Consistent with these observations, we here found that the frequency of CD8 + TILs in the neoplastic follicles was significantly higher in DTFL compared to LSFL and ASFL; this phenomenon may thereby be responsible for the more indolent clinical features of DTFL than LSFL and ASFL.…”

NUF2 Correlates with Poor Prognosis in Non-Small Cell Lung Cancer: A Systematic Multi-Omics Analysis

“…Another important aspect of this study was that the expression of NUF2 was correlated with the in ltration level of various immune cells in NSCLC. A large number of studies have explored immune cells in malignant tumor tissues to explore and their relationship with tumor occurrence, development and prognosis [29,30]. Immune cell in ltration in primary lung squamous cell carcinoma have a better prognosis [31].…”

Rituximab maintenance significantly reduces early follicular lymphoma progressions in patients treated with frontline R‐CHOP

“…Indeed, it separated a population with different biology and thus in need of a different treatment approach [16,17].…”