Immunotherapy – Biomechanisms
Ingrid Glimelius1, Rose-Marie Amini2, Beatrice Ginman1, Daniel Molin1, Gunilla Enblad1, Peter Hollander2
1 Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, 2 Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Background: High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated (reflecting the natural course) and treated (reflecting influence of treatment/relapse) cHL patients.
Patients and Methods: We screened pathology registers covering 3500 cHL patients, to identify patients that had removed a lymph node for other reasons prior to their cHL diagnose, and found 87 cases in three referral pathology centers in Sweden. These 87 biopsies were reviewed retrospectively and after review 11 of those patients had their benign lymph node biopsy reclassified as cHL. All those patients were untreated between the first and the diagnostic biopsy and designated as the untreated group. In addition, we identified thirty patients that had a primary and a relapse biopsy, designated as the treated. The paired biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. Differences in expression between biopsies were analyzed using Wilcoxon signed-rank test.
Results: In the untreated, 8 (73%) of 11 cases had an increased proportion of PD-L1+ leukocytes in biopsy 2 compared to biopsy 1, although none of the markers were statistically significantly different when biopsies 1 and 2 were compared (Figure 1). In the treated, 19 (63%), 22 (73%), and 18 (60%) of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively. When primary and relapse biopsies were compared, expression of PD-1+ leukocytes (p = 0.04), PD-L1+ leukocytes (p = 0.005) and PD-L1+ tumor cells (p = 0.009) was significantly higher in the relapse biopsies (Figure 1).
Conclusions: Our findings show that PD-1 and PD-L1 expression increases in relapsed cHL, most likely due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibition. In the untreated group an indication of up-regulation of the number of PD-L1+ cells in the microenvironment with time was seen, but did not reach statistical significance.