Ruxolitinib reverses checkpoint inhibition by reducing programmed cell death ligand‐1 (PD‐L1) expression and increases anti‐tumour effects of T cells in multiple myeloma

Abstract

Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.

Janus kinase 2 (JAK2) inhibitors in the treatment of multiple myeloma: modulating the myeloma immune microenvironment

“…32 Larger clinical trials of JAK inhibitors in patients with MM will inform us of the infection risk for patients with MM receiving JAK inhibitors in combination with other agents that increase risk of infection, such as corticosteroids, where increased risk of infection has been reported compared to patients only being treated with a JAK inhibitor. 33 The current paper by Chen et al (2020) 34 provides further supportive evidence for ruxolitinib modulating the myeloma microenvironment by blocking the programmed cell death ligand-1 (PD-L1) expression on myeloma tumour cells and increasing anti-myeloma T-cell cytotoxicity. Ruxolitinib reduces not only PD-L1 expression in myeloma tumour cells, but also downregulates PD-L1 expression in other non-tumoral cells and the study demonstrated the relationship of JAK/STAT signalling to regulation of PD-L1 expression.…”

“…The current paper by Chen et al . (2020) 34 provides further supportive evidence for ruxolitinib modulating the myeloma microenvironment by blocking the programmed cell death ligand‐1 (PD‐L1) expression on myeloma tumour cells and increasing anti‐myeloma T‐cell cytotoxicity. Ruxolitinib reduces not only PD‐L1 expression in myeloma tumour cells, but also downregulates PD‐L1 expression in other non‐tumoral cells and the study demonstrated the relationship of JAK/STAT signalling to regulation of PD‐L1 expression.…”

A Novel Necroptosis-Associated lncRNA Signature Can Impact the Immune Status and Predict the Outcome of Breast Cancer

“…For the expression level of the immune checkpoint, the high-risk group generally expressed less, such as CD274, CTLA4, and LAG3. Studies have shown that the lack of TIL and the deficiency of immune checkpoint expression are one of the reasons that lead to tumor insensitivity to ICI [ 51 ]. Inflammatory forms that trigger localized tumor necroptosis alter the tumor microenvironment and enhance the response to ICI [ 52 ].…”

PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review

“…NCT02871323 was withdrawn because of a low enrollment, while NCT01822509 assessed ipilimumab in comparison with nivolumab in phase 1 studies. Another two clinical trials were NCT03566446 (Phase I), a CALRLong36 peptide (exon 9 mut) vaccine trial, and NCT04051307, a PD-L1Long [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] ArgLong2 [ 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 ] vaccine trial; both studies were vaccine trials based on mutated calreticulin-induced T cell immunity [ 166 , 167 ]. No clinical trials using CPI in the treatment of myelofibrosis or MPN have been listed in 2022 (clinicaltrials.gov, accessed on 1 October 2018).…”

“…In multiple myeloma (MM), PD-L1 expression is increased in plasma cells from patients with MM compared with that from healthy donors, and its expression is associated with a resistance to a variety of anti-MM treatments. The reported inhibition of the PD-L1/PD-1 pathway in plasma cells by ruxolitinib [ 174 ] and decreased PMC-MDSC (LOX-1 expression) in Hodgkin’s lymphoma treated with a PD-1 inhibitor plus ruxolitinib [ 175 ] suggest that ruxolitinib may be a suitable candidate to be added to CPI therapy in the treatment of MPN, because ruxolitinib is expected to reduce PD-L1 expression in MDSCs. We also found that MDSCs in MPN show an increased PD-L1 expression [ 176 ], and ruxolitinib added to the CPI therapy may thus be a promising treatment option.…”