Using a customized time-of-flight mass cytometry (CyTOF) marker panel, Cader et al. confirmed that in classical Hodgkin lymphoma, the tumor microenvironment contains tumor cells with downregulated expression of β2M and MHC class I molecules, and revealed an enrichment of CD4+ T cells, which consist mostly of differentiated, Th1-polarized PD-1+ T effector cells and PD-1- Tregs. The differential PD-1 expression points to dual immunosuppression mechanisms – exhausted T effectors and activated Tregs.
In classical Hodgkin lymphoma (cHL), the host anti-tumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of the PD-1 ligands and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T-effectors (Teff). However, durable responses are observed in patients with beta2M/MHC class I loss on HRS cells, raising the possibility of non-CD8(+) T cell-mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry (CyTOF) panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4(+) T-cell rich with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of Th1-polarized Teff and regulatory T cells (Treg). The cHL Th1 Tregs expressed little or no PD-1 while the Th1 Teffs were PD-1(+) The differential PD-1 expression and likely functional Th1-polarized CD4(+) Tregs and exhausted Teff may represent complementary mechanisms of immunosuppression in cHL.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (2) Department of Cell Biology, Harvard Medical School, Boston, MA, United States. (3)
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (2) Department of Cell Biology, Harvard Medical School, Boston, MA, United States. (3) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Harvard T.H. Chan School of Public Health, Boston, MA, United States. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (5) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Harvard T.H. Chan School of Public Health, Boston, MA, United States. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (8) Longwood Medical Area CyTOF Core Facility, Dana-Farber Cancer Institute, Boston, MA, United States. (9) Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. (10) Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States. (12) Department of Pathology, University of Washington, Seattle, WA, United States. (13) Department of Pathology, University of Washington, Seattle, WA, United States. (14) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Harvard T.H. Chan School of Public Health, Boston, MA, United States. (15) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Harvard T.H. Chan School of Public Health, Boston, MA, United States. (16) Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; margaret_shipp@dfci.harvard.edu.
