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Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade.

ABSTRACT: Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that tumor-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8⁺ and CD4⁺ T cells and M1-biased macrophages) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. Then, a neutralizing antibody against IL-34 improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy.

SUBMITTER: Hama N

PROVIDER: S-EPMC7648133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeDexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.Experimental designWe evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.ResultsDespite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16; P = 0.005].ConclusionsOur preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

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Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade.

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