In the majority of human tumors, downregulation of major histocompatibility complex class I (MHC‑I) expression contributes to the escape from the host immune system and resistance to immunotherapy. Relevant animal models are therefore needed to enhance the efficacy of cancer immunotherapy. As loss of β‑2 microglobulin expression results in irreversible downregulation of surface MHC‑I molecules in various human tumors, the β‑2 microglobulin gene (B2m) was deactivated in a mouse oncogenic TC‑1 cell line and a TC‑1/dB2m cell line that was negative for surface MHC‑I expression was derived. Following stimulation with interferon γ, MHC‑I heavy chains, particularly the H‑2Db molecules, were found to be expressed at low levels on the cell surface, but without β‑2 microglobulin. B2m deactivation in TC‑1/dB2m cells led to reduced proliferation and tumor growth. These cells were insensitive to DNA vaccination and only weakly responsive to combined immunotherapy with a DNA vaccine and the ODN1826 adjuvant. In vivo depletion demonstrated that NK1.1+ cells were involved in both reduced tumor growth and an antitumor effect of immunotherapy. The number of immune cells infiltrating TC‑1/dB2m‑induced tumors was comparable with that in tumors developing from TC‑1/A9 cells characterized by reversible MHC‑I downregulation. However, the composition of the cell infiltrate was different and, most importantly, infiltration with immune cells was not increased in TC‑1/dB2m tumors after immunotherapy. Therefore, the TC‑1/dB2m cell line represents a clinically relevant tumor model that may be used for enhancement of cancer immunotherapy.
- MeSH
- beta-2-mikroglobulin genetika imunologie MeSH
- cytotoxické T-lymfocyty imunologie patologie MeSH
- histokompatibilita - antigeny třídy I genetika imunologie MeSH
- imunoterapie MeSH
- interferon gama imunologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie metabolismus MeSH
- nádory genetika imunologie patologie MeSH
- regulace genové exprese u nádorů genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.
- MeSH
- antigeny CD274 antagonisté a inhibitory biosyntéza genetika imunologie MeSH
- antigeny CD279 antagonisté a inhibitory biosyntéza genetika imunologie MeSH
- beta-2-mikroglobulin biosyntéza genetika imunologie MeSH
- buňky Reedové-Sternberga účinky léků imunologie patologie MeSH
- doba přežití bez progrese choroby MeSH
- histokompatibilita - antigeny třídy II biosyntéza genetika imunologie MeSH
- Hodgkinova nemoc farmakoterapie genetika imunologie patologie MeSH
- kohortové studie MeSH
- lidé MeSH
- lidské chromozomy, pár 9 MeSH
- nivolumab terapeutické užití MeSH
- prediktivní hodnota testů MeSH
- prezentace antigenu MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- beta-2-mikroglobulin chemie imunologie MeSH
- biomedicínský výzkum MeSH
- histokompatibilita - antigeny třídy I imunologie metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- leukocyty mononukleární imunologie účinky léků MeSH
- lidé MeSH
- lymfocyty imunologie MeSH
- monoklonální protilátky imunologie metabolismus MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- Check Tag
- lidé MeSH
Acta dermato-venereologica, ISSN 0365-8341 ; suppl. 94
40 s. ; 26 cm