Open AccessProgression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration
Author(s) -
Joshua W.D. Tobin,
Colm Keane,
Jay Gunawardana,
Peter Mollee,
Simone Birch,
Thị Thu Hương Hoàng,
Justina Lee,
Li Li,
Li Huang,
Valentine Murigneux,
J. Lynn Fink,
Nicholas Matigian,
Frank Vari,
Santiyagu M. Savarimuthu Francis,
Robert Kridel,
Oliver Weigert,
Sarah Haebe,
Vindi Jurinović,
Wolfram Klapper,
Christian Steidl,
Laurie H. Sehn,
Soi Cheng Law,
Michelle Wykes,
Maher K. Gandhi
Publication year - 2019
Publication title -
journal of clinical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.482
H-Index - 548
eISSN - 1527-7755
pISSN - 0732-183X
DOI - 10.1200/jco.18.02365
Subject(s) - immune system , follicular lymphoma , medicine , immunology , vincristine , immune checkpoint , lymphoma , immunophenotyping , rituximab , immunotherapy , cancer research , cyclophosphamide , flow cytometry , chemotherapy
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 infiltration HI (ie, high PD-L2) FL biopsies from immune infiltration LO (ie, low PD-L2) tumors. Immune infiltration HI tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. Of note, the immune infiltration LO 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.