Therapeutic targets and microenvironment in sequential biopsies of classical Hodgkin lymphoma at diagnosis and relapse

Abstract

Classical Hodgkin lymphoma is dominated by the non-neoplastic microenvironment, while the neoplastic Hodgkin-Reed-Sternberg cells compose only a minority of cells in the lymphoma tissue. Both the Hodgkin-Reed-Sternberg cells due to their expression of CD30 and PD-L1 and the microenvironment with abundant T cells and expression of PD1 are specifically targeted by new treatment concepts. We aimed to understand the dynamics of therapeutic targets in patients treated with conventional chemotherapy. We analyzed sequential biopsy specimens obtained at diagnosis and at relapse from the same patient for morphology, immunophenotype, and microenvironmental components. The morphological subtype changed between primary and relapse biopsy in 20% of cases. The immunophenotype was stable with respect to CD30, CD3, and LMP1 but variable with respect to CD15 and CD20 expression. Gene expression revealed 8 upregulated and 20 downregulated genes at relapse (p ≤ 0.05) with a consistent logarithmic fold change direction in at least 75% of all cases. For PD1, we found discrepant results between gene expression analysis (decrease at relapse) and number of PD1-positive cells assessed by immunohistochemistry (unchanged at relapse). PD-L1 in the neoplastic cells appeared unchanged between primary diagnosis and relapse. The expression of the therapeutic targets CD30, PD1, and PD-L1 can reliably be assessed in tumor specimen at first diagnosis and is unchanged under conventional chemotherapy.

Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1

“…Of note, the alteration in PD1/PD-L1 expression in the tumor microenvironment seems to be specific for relapses under anti-PD1 treatment and has not been observed in relapses after conventional therapy. 13,29,32 It remains unknown whether the observed disturbance in the microenvironment with respect to PD1/PD-L1 reflects HRSCs being less competent in modeling the microenvironment or less dependent on the specific microenvironmental composition.…”

“…The average value of 2 independent fields of view was calculated as previously described. 13 Expression of b2-microglobulin and HLA-DP was scored by counting the number of HRSCs in the high-power field with membrane or cytosolic staining, as previously described. 2 Samples were defined as positive if the majority of HRSCs had membrane staining, they were defined as negative if no HRSC had membrane staining, they were defined as partially positive if only a few HRSCs had membrane staining, and they were defined as cytoplasmic only if only cytoplasmic staining was observed.…”

Histological Subtypes Drive Distinct Prognostic Immune Signatures in Classical Hodgkin Lymphoma

“…Genes downregulated at diagnosis in r/r cHL patients compared to non-r/r patients were mostly related to B-cell differentiation or activation. Among them, CD79A, MS4A1, CD74, CD81 genes have already been identified as favorable prognosis factors in cHL patients [20][21][22][23][24]. Indeed, it has been demonstrated that loss of B-lineage identity allows HRS cells to survive in the absence of BCR signaling, and prevents the induction of apoptosis [25,26].…”

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

“…We examined the immune checkpoints expression and the number of TAMs in a cohort of 15 patients with primary and in repeated samples after immunotherapy failure and found the enrichment of PD-1-positive and LAG-3-positive cells and depletion of TAMs (CD163, CD68-positive cells). In previously published studies, several researchers found increasing levels of PD-1-positive T cells in cHL at relapse after standard chemotherapy by the immunohistochemical method [ 61 ], while in other reports, changes in PD-1-positive cell counts at relapse were not found by immunohistochemical or gene expression analysis [ 62 , 63 ]. In the analysis of the specimens at relapse in patients receiving standard chemotherapy, Schnitter et al found no evidence of enrichment of TAMs (CD163-positive cells) [ 62 ].…”

“…In previously published studies, several researchers found increasing levels of PD-1-positive T cells in cHL at relapse after standard chemotherapy by the immunohistochemical method [ 61 ], while in other reports, changes in PD-1-positive cell counts at relapse were not found by immunohistochemical or gene expression analysis [ 62 , 63 ]. In the analysis of the specimens at relapse in patients receiving standard chemotherapy, Schnitter et al found no evidence of enrichment of TAMs (CD163-positive cells) [ 62 ]. The expression markers or cell composition may change when patients receive immunotherapy.…”