Clinicopathological analysis of immunohistochemical expression of immune checkpoint molecules in follicular lymphoma

• Published in: Hematological oncology 2022-10, Vol.40 (4), p.530-540
• Main Authors: Yanagida, Eriko, Miyoshi, Hiroaki, Takeuchi, Mai, Shimono, Joji, Nakashima, Kazutaka, Yamada, Kyohei, Kawamoto, Keisuke, Moritsubo, Mayuko, Shimasaki, Yasumasa, Inoue, Kanako, Imamoto, Teppei, Furuta, Takuya, Kohno, Kei, Ohshima, Koichi
• Format: Article
• Language: English
• Subjects: Abnormalities; Apoptosis; Biopsy; CD86 antigen; Cell death; Cytoplasm; follicular lymphoma; Gene expression; Immune checkpoint; immune checkpoint molecule; Immunohistochemistry; Leukemia; Lymphoma; Medical prognosis; Microenvironments; Ox40L protein; pathology; PD-L1 protein; Stromal cells; Tumor cells; Tumor necrosis factor; Tumors
• ISSN: 0278-0232; 1099-1069
• DOI: 10.1002/hon.2972

Follicular lymphoma (FL) is characterized by an indolent clinical course and a high relapse rate, and often exhibits a diffuse pattern beyond the follicular area. Our group previously reported that immune checkpoint (ICP) pathways, such as programmed cell death (PD‐1) and programmed death ligand 1 (PD‐L1), are poor prognostic factors for diffuse large B‐cell lymphoma and adult T‐cell leukemia/lymphoma. In this study, the association between the expression of multiple ICP molecules according to immunohistochemistry and clinicopathological features in FL was determined via immunostaining of 173 biopsy samples. Membrane and/or cytoplasm expression of CD86 (nCD86) and PD‐L1 (nPD‐L1) was found in tumor cells, whereas PD‐1 (miPD‐1), Galectin‐9 (miGalectin‐9), OX40 (miOX40), CTLA‐4 (miCTLA‐4), Tim‐3 (miTim‐3), OX40L (miOX40L), and LAG‐3 (miLAG‐3) were expressed in non‐neoplastic stromal cells. MiPD‐1 expression was significantly higher in the follicular area than in the diffuse area (p = 0.0450). Expression of miOX40 and miCTLA‐4 was significantly higher in the diffuse area than in the follicular area (respectively, p = 0.0053 and p = 0.0092). MiTim‐3 tended to be higher in the diffuse area than in the follicular area (p = 0.0616). MiTim‐3 was significantly higher in relapse cases than in new‐onset cases (p = 0.0440); miLAG‐3 tended to be higher in relapse cases than in new‐onset cases (p = 0.0622, not significant). The miOX40L‐high FL group had a significantly worse overall survival than the miOX40L‐low group (p = 0.0320). The expression of multiple ICP molecules on several cells reflects activated anti‐tumor immunity and the unique FL microenvironment. Further studies on gene expression or genomic abnormalities will reveal the clinical and biological significance of ICP molecules in FL.