Abstract Immunomodulation and tumor-induced tolerance is one of the central mechanisms in the oncogenesis of malignant and benign neoplasms. While numerous pathways have been described, signaling through the programmed death receptor 1 (PD-1) on T lymphocytes, via activation through its ligand, programmed death ligand 1 (PD-L1) expressed on tumor cells is one of the central pathways involved in tumor-induced tolerance. While the neoplastic component of germinomas of the CNS is the germ cell, these tumors also exhibit an abundance of quiescent tumor-infiltrating lymphocytes. We therefore investigated whether PD-L1 expression may be responsible for germinoma-induced T cell anergy, and if these tumors may be susceptible to immunotherapy. Pathologic specimens obtained from 21 cases of CNS germinomas between 2000 and 2016 were analyzed for the presence of PD-L1 and PD-1 expression by immunohistochemistry. Nineteen of 21 germinomas (90%) harbored germ cell components that stained positively for PD-L1. Positive lymphocyte staining for PD-L1 was evident in 16 cases. PD-1 expression was largely confined to lymphocytes; PD-L1 therefore may contribute to lymphocyte quiescence observed in these tumors. These results raise the possibility that immune checkpoint inhibitors such as nivolumab may have a therapeutic role in future treatment of germinomas. Checkpoint inhibitors, Germinoma, Immunotherapy, Neuro-oncology, Programmed death ligand 1 INTRODUCTION Intracranial germinomas are a rare manifestation of extragonadal germ cell tumors with a reported incidence of less than 0.1 cases per 100 000 person years (1). These tumors, commonly arising in the suprasellar or pineal region, disproportionately affect adolescents and account for approximately 3%–5% of diagnosed pediatric brain tumors (1–4). Germinomas of the CNS are highly radiosensitive and historically 10-year overall survival rates in excess of 95% have been reported with irradiation, either craniospinal or whole ventricular with a boost to the primary site (5, 6). Nevertheless, as concerns have been voiced regarding the long-term efficacy and deleterious sequela of radiation in young patients, the optimal management of germinomas remains controversial (7–9). As a result, several authors have investigated radiation dose reduction with neoadjuvant chemotherapy (10–12). Nevertheless, germinomas have shown only marginal response rates to isolated chemotherapeutic strategies thereby reinforcing radiation as the primary treatment modality for these benign neoplasms of adolescence (13). As such, an improved understanding of germinoma tumorigenesis is necessary in order to guide novel treatment strategies for these rare tumors. Germinomas exhibit an abundance of tumor-infiltrating lymphocytes on histologic analysis (14). Paradoxically, the tumor-infiltrating lymphocytes observed in germinoma specimens appear to be quiescent, without any notable antitumor effect, although this finding has been disputed (15–19). It has been recently reported that testicular seminomas, the gonadal counterpart to CNS germinomas, express programmed death ligand 1 (PD-L1) (20). PD-L1, also referred to as CD274, binds to the programmed death receptor 1 (PD-1) on activated lymphocytes, leading to downregulation of the immune response. Indeed, interaction of PD-L1 with PD-1 has emerged as a critical pathway observed in tumor-induced tolerance (21). Given the brisk but apparently anergic infiltrate of lymphocytes observed in CNS germinomas, we investigated whether these tumors express PD-L1. MATERIALS AND METHODS The study was approved by the Institutional Review Board of the University of Virginia Health System. Pathologic specimens from 21 patients (15 male, 6 female) who were diagnosed with CNS germinomas between 2000 and 2016 were retrieved from our institution files. The mean age of patients in our series was 19.6 years (range 9–34 years). Tumors originated from the pineal gland (n = 10), suprasellar region (n = 9), lateral ventricle (n = 1), or adjacent to the cerebral aqueduct (n = 1). A tissue microarray was prepared from optimal sampling sites. Due to the small size of both pineal and pituitary biopsies, only one 1.5-mm core was obtained for the tissue microarray. One of the cases contained no visible tumor, and thus immunohistochemical analysis was performed on 21 cases. Five nongerminomatous germ cell tumors, 1 lymphohistiocytic infiltrate, and 1 Langerhans cell histiocytosis furnished control cores. Immunohistochemical staining for PD-L1/CD274 (SP142, Spring Bioscience, Pleasanton, CA, undiluted, on the Leica Bond III platform, Buffalo Grove, IL) was performed on the microarray. Immunohistochemical staining for PD-1 (NAT105, Abcam #ab52587, Cambridge, MA, dilution 1: 300, on the Leica Bond III) was also performed on the microarray. Immunostaining for OCT3/4 was done on all cases to confirm the presence of germinoma. PD-L1 staining was scored in both germ cells and lymphocytes, and the extent of staining was ranked in 5 subgroups: (1) 1%–5%; (2) 6%–10%; (3) 11%–25%; (4) 26%–50%; and (5) greater than 50%. We considered positive expression to be membranous staining in 1% or more of the tumor cells, based on procedure frequently followed in treating nonsmall cell lung cancer (NSCLC) (22). PD-1 staining was scored similarly. RESULTS The presence of germinoma was confirmed by histologic analysis and was corroborated by positive nuclear staining for OCT3/4 in all 21 cores (Fig. 1A, B). Nineteen of 21 germinomas (90%) showed appreciable germ cell membranous and/or granular cytoplasmic positivity for PD-L1 with the SP142 antibody using the Leica Bond platform as summarized in the Table and Figure 1C. Of those germinomas with PD-L1 positivity, 37% (7/19) showed >50% staining; 5% (1/19) showed 26%–50%; 21% (4/19) showed 11%–25%; 26% (5/19) cases showed 6%–10%, and 11% (2/19) cases showed 1%–5%. In the 2 germinomas without definitive PD-L1 staining, one case showed a diffuse blush staining pattern, and 1 case was negative for PD-L1. Regarding staining for PD-L1 in tumor-associated lymphocytes, definite PD-L1 staining was seen in only one of the 21 specimens (Fig. 1D), while a diffuse blush was observed in 15/21 cases (Fig. 1E). FIGURE 1. View largeDownload slide (A) CNS germinoma, H&E, 20×; (B) germ cells highlighted by OCT3/4 (20×); (C) PD-L1 expression in germ cells (20×); (D) PD-L1 expression in tumor-infiltrating lymphocytes (20×); (E) diffuse blush expression of PD-L1 in lymphocytes (20×); (F) stromal expression of PD-1 (20×). FIGURE 1. View largeDownload slide (A) CNS germinoma, H&E, 20×; (B) germ cells highlighted by OCT3/4 (20×); (C) PD-L1 expression in germ cells (20×); (D) PD-L1 expression in tumor-infiltrating lymphocytes (20×); (E) diffuse blush expression of PD-L1 in lymphocytes (20×); (F) stromal expression of PD-1 (20×). Reactivity for PD-1 was observed in 10/21 (48%) germinomas, a rate less common than for PD-L1. PD-1 expression was predominantly seen in lymphocytes or tumor-associated stromal cells. Of the cases that did show positive staining, one was positive in 11%–25% of the stromal/immune compartment (Fig. 1F), one in 6%–10%, and 8 in 1–5%. Neither age nor gender correlated with intensity of staining for either PD-L1 or PD-1. DISCUSSION PD-1 is a transmembrane receptor situated on CD4+ and CD8+ lymphocytes and constitutive activation of this receptor by its ligand, PD-L1, leads to reduced secretion of proinflammatory cytokines and cytolytic effectors by lymphocytes (23). Regulatory T cells similarly express PD-1 and have been shown to downregulate the immune response and induce tolerance when activated by PD-L1 (23). In this way, activation of PD-1 via PD-L1 leads to suppression of effector lymphocyte function while promoting immunosuppressive regulatory T cell activity. While PD-1 activation is important in establishing tolerance throughout the immune system, tumor-induced tolerance by expression of PD-L1 has been described in melanoma, breast cancer, NSCLC, renal cell carcinoma, and most recently testicular germ cell tumors (20, 24–27). Indeed, tumor-induced lymphocyte anergy has been associated with more aggressive tumors, and PD-L1 expression has been shown to be associated with a poor prognosis in melanoma, NSCLC, breast cancer, and glioblastoma (28–31). Likewise, tumors that harbor tumor-infiltrating lymphocytes with increased PD-1 expression have been suggested to be more aggressive (21). It is therefore not surprising that there has been an emerging focus on modulating the interaction between PD-1 and PD-L1 by checkpoint inhibitors such as nivolumab (32). Nivolumab has been shown in 2 separate randomized controlled trials to increase overall survival in patients with advanced NSCLC and is currently FDA approved for use in advanced melanoma and NSCLC (33, 34). Thus, the identification of PD-L1 expression by different neoplasms aids in the understanding of tumorigenesis while affording the opportunity for the development of novel therapeutic strategies. Although germinomas are radiosensitive neoplasms, their predilection to occur in adolescents and young adults has heightened attention to long-term tumor recurrence rates and remote radiation side effects (8, 9). Acharya et al analyzed patients with CNS germinomas who had achieved greater than 5-year overall survival (8). In their analysis, those with long-term survival had a 10-fold increase in overall mortality (often secondary to recurrent disease) compared to age-matched individuals without a history of CNS germinoma. Radiation-related side effects were apparent with patients harboring a 59-fold increase in stroke-related mortality and a striking number of patients who developed secondary brain tumors. As such, additional treatment strategies for germinomas are needed. Herein we describe a series of 21 patients who had biopsy-proven CNS germinomas. Immunohistochemical investigation showed that 90% of pathologic specimens expressed PD-L1. Our results are similar to the series described by Fankhauser et al who detailed the presence of PD-L1 staining in 73% of sampled seminomas (20). Thus PD-L1 expression by germ cells may explain the otherwise ubiquitous, inert lymphocyte infiltrate observed in these tumors. At odds with our findings, Aoki et al recently reported that PD-L1 expression was not observed in 7 pediatric germinoma specimens (35). While small sample sizes and different patient populations may account for the discrepancies with our study, they found PD-L1 expression to be confined to macrophages, whereas we clearly show its presence in germ cells within the tumor (Fig. 1C). With regard to the indistinct or blush staining of lymphocytes, which varied in intensity among samples, we believe it may be due to tissue surgical compression. It appears to indicate positivity for PD-L1 in tumor-associated lymphocytes, stromal cells and (possibly) macrophages, although staining for specific cell types was not practicable, given the limited amount of tissue available. Nonetheless, we believe that the variable blush staining for PD-L1 present in the lymphocyte/stromal compartment is real and significant in terms of potential response to targeted therapy. Our study has several limitations. One is the relatively small number of germinomas available to us. Additionally, given that germinomas are biopsied, not fully resected, there was limited tissue available for detailed immunohistochemical analysis. Thus, our analysis was performed on a portion of the entire germinoma, which may partially account for the varying results obtained by our work and Aoki et al (35). Another limitation is the somewhat arbitrary choice of antibody used to assess PD-L1. Currently, many antibodies for detecting PD-L1 are in use. For example, Aoki’s study used the anti-PD-L1 clone E1L3N (Cell Signaling Technology, Danvers, MA), and considered membrane staining of >5% of the cells to be a positive result for expression of PD-L1 in a given specimen. Given that there is presently no FDA requirement for a specific PD-L1 clone in germinoma, we chose to use the SP142 antibody because it has produces crisp linear membrane staining when used in other contexts in our laboratory (36). PD-L1 (SP142 using Leica Bond III) methods have been validated internally in our laboratory against the 22C3 antibody (Dako) at a cutoff of 50% staining (97% concordance). Moreover, it was developed as a companion assay for the anti-PD-L1 agent atezolizumab in the setting of nonsmall cell lung carcinoma, where it is used to evaluate PD-L1 activity in both tumor and immune compartments (37). However, one study has shown SP142 to yield the least reproducible results of 4 anti-PD-L1 antibodies (38). A third difficulty is the challenge of precisely localizing both PD-L1 and PD-1 activity within the stromal/immune compartment of the tumor. PD-L1 is known to be expressed by many types of cells involved in immune responses, including activated T cells, B cells, macrophages, dendritic cells, and mesenchymal stem cells (39). However, the clinical significance of the distribution of PD-L1 expression among tumor cells and the various immune cells has yet to be clarified (40). Additional investigation, perhaps incorporating immunohistochemistry, immunofluorescence, or other tools, seems called for. In spite of these limitations, however, our work at minimum suggests that PD-L1 expression is common in the germ cell compartment of CNS germinomas. In view of the fact that PD-L1 expression by tumor cells attenuates the antitumoral immune response in several ways, immune checkpoint inhibitors may have a role in the therapeutic approach to these tumors. In this respect, we concur with Fankhauser et al who concluded on the basis of their findings that a trial of immune blockade may be warranted in testicular seminomas, and by extension, germinomas (20). TABLE. Expression of PD-1 and PD-L1 in Tumor Cells and Lymphocytes Cases Age/Sex Location Tumor Type PD-L1, Tumor Cells PD-L1, Lymphocytes PD-1 1 13/M Pineal Germinoma/yolk sac 3 Blush Negative 2 24/F Sella Germinoma 2 Blush Negative 3 17/F Sella Germinoma 3 Blush 3 4 19/M Pineal Germinoma 3 Blush Negative 5 24/M Pineal Germinoma 1† Blush Negative 6 15/M Left lateral ventricle Germinoma Blush Negative Negative 7 21/M Suprasellar Germinoma 1 Blush Negative 8 34/M Pineal Germinoma 5 Blush Negative 9 10/F Sella/suprasellar Germinoma 3 2 Negative 10 10/F Sella Germinoma 5 Negative 2 11 28/M Pituitary stalk Germinoma 5 Negative 1 12 13/F Sella Germinoma 2 Blush 1 13 19/F Suprasellar Germinoma 2 Blush 1 14 22/M Periaqueductal Germinoma 4–5 Blush 1 15 16/M Pineal Germinoma 5 Blush Negative 16 15/M Pineal Germinoma 5 Blush Negative 17 15/M Pineal Germinoma 2 Negative Negative 18 34/M Pineal Germinoma 5 Negative 1 19 34/M Pineal Germinoma 2 Blush 1 20 19/M Suprasellar Germinoma 5 Blush 1 21 9/M Pineal Germinoma/mixed* Negative Blush 1 Controls A 11/F Sella Malignant mixed GCT Negative Negative ND B 43/F Right temporal Choriocarcinoma 2 1 ND C 38/F Suprasellar Mature teratoma Negative Negative ND D 24/M Pineal Lymphohistiocytic infiltrate Blush Negative ND E 60/M Left frontal Immature teratoma Negative Negative ND F 49/M T1/epidural Malignant mixed GCT Negative Negative ND G 34/M Pituitary stalk Langerhans histiocytosis Negative Negative ND Cases Age/Sex Location Tumor Type PD-L1, Tumor Cells PD-L1, Lymphocytes PD-1 1 13/M Pineal Germinoma/yolk sac 3 Blush Negative 2 24/F Sella Germinoma 2 Blush Negative 3 17/F Sella Germinoma 3 Blush 3 4 19/M Pineal Germinoma 3 Blush Negative 5 24/M Pineal Germinoma 1† Blush Negative 6 15/M Left lateral ventricle Germinoma Blush Negative Negative 7 21/M Suprasellar Germinoma 1 Blush Negative 8 34/M Pineal Germinoma 5 Blush Negative 9 10/F Sella/suprasellar Germinoma 3 2 Negative 10 10/F Sella Germinoma 5 Negative 2 11 28/M Pituitary stalk Germinoma 5 Negative 1 12 13/F Sella Germinoma 2 Blush 1 13 19/F Suprasellar Germinoma 2 Blush 1 14 22/M Periaqueductal Germinoma 4–5 Blush 1 15 16/M Pineal Germinoma 5 Blush Negative 16 15/M Pineal Germinoma 5 Blush Negative 17 15/M Pineal Germinoma 2 Negative Negative 18 34/M Pineal Germinoma 5 Negative 1 19 34/M Pineal Germinoma 2 Blush 1 20 19/M Suprasellar Germinoma 5 Blush 1 21 9/M Pineal Germinoma/mixed* Negative Blush 1 Controls A 11/F Sella Malignant mixed GCT Negative Negative ND B 43/F Right temporal Choriocarcinoma 2 1 ND C 38/F Suprasellar Mature teratoma Negative Negative ND D 24/M Pineal Lymphohistiocytic infiltrate Blush Negative ND E 60/M Left frontal Immature teratoma Negative Negative ND F 49/M T1/epidural Malignant mixed GCT Negative Negative ND G 34/M Pituitary stalk Langerhans histiocytosis Negative Negative ND Key to PD-L1 and PD-1 scoring: blush = diffuse faint staining; 1 = 1%–5% positive; 2 = 6%–10% positive; 3 = 11%–25% positive; 4 = 26%–50% positive; 5 = > 50% positive. 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Journal of Neuropathology & Experimental Neurology – Oxford University Press
Published: Apr 1, 2018
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