Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma

Antonios, Joseph; Soto, Horacio; Everson, Richard; Moughon, Diana; Orpilla, Joey; Shin, Namjo; Sedighim, Shaina; Treger, Janet; Odesa, Sylvia K.; Tucker, Alexander M.; Yong, William H.; Li, Gang; Cloughesy, Timothy F.; Liau, Linda M.; Prins, Robert M.

doi:10.1093/neuonc/now287

Cited by 138 publications

(147 citation statements)

References 47 publications

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“…One critical mediator of immunosuppression in GBM is PD-L1 (37,38). While only a fraction of GBM cells express PD-L1 (15,16), myeloid cells in the tumor microenvironment and circulation abundantly express PD-L1 (40). Immunosuppressive myeloid cells are of particular importance in GBM as they extensively infiltrate tumors (26,27) and correlate with decreased survival (28,54).…”

Section: Discussionmentioning

confidence: 99%

“…While normally involved in immune homeostasis, in the setting of malignancy, PD-L1 can interact with its receptor, programmed death-1 (PD-1), expressed on activated T cells, to induce T-cell anergy or apoptosis (37)(38)(39). Although PD-L1 is expressed on tumor cells (15,16), evidence suggests that myeloid PD-L1 may contribute more to the suppression of antitumor T cells (40). We have previously reported that elevated peripheral myeloid PD-L1 was associated with reduced response to vaccine immunotherapy and worse survival in patients with GBM (25).…”

Section: Introductionmentioning

confidence: 99%

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Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Lamano

et al. 2019

Clinical Cancer Research

142

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Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design: Conditioned media from patientderived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate na€ ve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8 þ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001; ÃÃÃÃ , P < 0.0001.Lamano et al. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Lamano

et al. 2019

Clinical Cancer Research

142

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“…C /PD1 C Tregs could be either minor enforcers of immunosuppression 41 or susceptible to being replaced by T cells expressing alternative immune checkpoints following ICIs treatment. For instance, a recent preclinical study found T cells exploiting T-cell immunoglobulin mucin-3 (TIM3) to drive lung cancer growth despite anti-PD1 therapy.…”

Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

et al. 2017

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Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM.

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“…Additionally, numerous other preclinical studies have highlighted the tumor-promoting and immunosuppressive roles of these cells in GBM [2,[24][25]. However, unlike promising preclinical studies, efforts to deplete TAMCs in GBM patients have been disappointing.…”

Section: Discussionmentioning

confidence: 99%

Preclinical immunoPET imaging of glioblastoma-infiltrating myeloid cells using Zirconium-89-labeled anti-CD11b antibody

Nigam

McCarl

Kumar

et al. 2019

Preprint

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Purpose. Glioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). TAMCs are emerging as a promising therapeutic target as they suppress antitumor immune responses and promote tumor cell growth. Quantifying TAMCs using non-invasive immunoPET could facilitate patient stratification for TAMC-targeted treatments and monitoring of treatment efficacy. As TAMCs uniformly express the cell surface marker, integrin CD11b, we evaluated a 89 Zr-labeled anti-CD11b antibody for non-invasive imaging of TAMCs in a syngeneic orthotopic mouse glioma model. Procedures.A human/mouse cross-reactive anti-CD11b antibody (clone M1/70) was conjugated to a DFO chelator and radiolabeled with Zr-89. PET/CT and biodistribution with or without a blocking dose of anti-CD11b Ab were performed 72 hours post-injection of 89 Zr-anti-CD11b Ab in mice bearing established orthotopic syngeneic GL261 gliomas. Flow cytometry and immunohistochemistry of dissected GL261 tumors were conducted to confirm the presence of CD11b + TAMCs.Results. Significant uptake of 89 Zr-anti-CD11b Ab was detected at the tumor site (SUVmean = 2.60 ± 0.24) compared with the contralateral hemisphere (SUVmean = 0.6 ± 0.11). Blocking with a 10-fold lower specific activity of 89 Zr-anti-CD11b Ab markedly reduced the SUV in the right brain (SUVmean = 0.11 ± 0.06), demonstrating specificity. Spleen and lymph nodes (myeloid cell rich organs) also showed high uptake of the tracer, and biodistribution analysis correlated with the imaging results. CD11b expression within the tumor was validated using flow cytometry and immunohistochemistry, which showed high CD11b expression primarily in the tumoral hemisphere compared to the contralateral hemisphere.3 Conclusion. These data establish that 89 Zr-anti-CD11b Ab immunoPET targets CD11b + cells (TAMCs) with high specificity in a mouse model of GBM, demonstrating the potential for noninvasive quantification of tumor infiltrating CD11b + immune cells during disease progression and immunotherapy in patients with GBM.

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Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma

Cited by 138 publications

References 47 publications

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

Preclinical immunoPET imaging of glioblastoma-infiltrating myeloid cells using Zirconium-89-labeled anti-CD11b antibody

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