Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations

SIMPLE SUMMARY: Classic Hodgkin lymphoma contains rare malignant Hodgkin/Reed–Sternberg cells and abundant reactive populations in the tumor microenvironment. Many aspects of the interaction between tumor cells and immune cells remain unclear. Nevertheless, the microenvironment is believed to play a crucial role in tumor resistance and progression. Current knowledge about the role and dynamics of the tumor microenvironment in Hodgkin lymphoma during anti-PD-1 treatment is limited. The aim of this study was to identify possible predictive and prognostic morphological markers in the treatment of patients with relapsed or refractory classic Hodgkin lymphoma treated with nivolumab and to assess the variability of reactive cell populations after nivolumab therapy. The study was aimed to optimize therapeutic strategy in patients with relapsed or refractory classic Hodgkin lymphoma. ABSTRACT: To date, the impact of the tumor microenvironment on the prognosis of patients with classic Hodgkin lymphoma (cHL) during anti-PD-1 therapy has been studied insufficiently. This retrospective study included 61 primary samples of lymph nodes from patients who had relapsed/refractory (r/r) cHL and were treated with nivolumab. Repeated samples were obtained in 15 patients at relapse or disease progression after immunotherapy. Median follow-up was 55 (13–63) months. The best overall response rate and progression-free survival (PFS) were analyzed depending on the expression of CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT, CD163/c-maf in the tumor microenvironment in primary and sequential biopsies. The combination of CD163/c-maf antibodies was used for the identification of M2 macrophages (M2). A low number of macrophages in primary samples was associated with inferior PFS during nivolumab treatment (for CD163-positive cells p = 0.0086; for CD68-positive cells p = 0.037), while a low number of M2 with higher PFS (p = 0.014). Complete response was associated with a lower level of M2 (p = 0.011). In sequential samples (before and after nivolumab therapy) an increase in PD-1 (p = 0.011) and LAG-3 (p = 0.0045) and a depletion of CD68 (p = 0.057) and CD163 (p = 0.0049)-positive cells were observed. The study expands understanding of the cHL microenvironment structure and dynamics during nivolumab therapy in patients with r/r cHL.