The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Editor-in-Chief, Pedro J. Romero, MD.
“Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal” by Tobias Baumann et al
Myeloid-derived suppressor cells (MDSCs) inhibit cytotoxic T cell activity within tumors, and a lack of definitive surface markers for these populations has made the mechanisms by which they inhibit anti-cancer immunity difficult to study. Tobias Baumann and colleagues identify methylglyoxal as a metabolic marker of MDSCs and uncover a role for the metabolite in T cell suppression. T cells activated in contact with MDSCs in vitro did not increase glucose uptake and activation-induced phosphorylation of key protein kinases downstream of the T cell receptor was almost completely abolished. Transfer of cytosolic constituents between MDSCs and T cells was detected both in vitro and in vivo, and treatment with dimethylbiguanide (DMBG), but not rotenone, reverted the suppressive phenotype—implying a function distinct from mitochondrial respiration. Through metabolite analysis by ultrahigh performance liquid chromatography with time-of-flight tandem mass spectrometry and data independent acquisition, methylglyoxal was found to be 30-fold enriched in MDSCs. Furthermore, within 10 minutes after contact with MDSCs but not monocytes, methylglyoxal was detectable in CD8+ T cells. Methylglyoxal reacts with l-arginine, and a complete reduction in free l-arginine in T cells was observed after co-culture with MDSCs. Competitive pulse-chase labeling experiments revealed the source of methylglyoxal in MSDCs to be semicarbazide-sensitive amine oxidase. In mouse models of melanoma, separate treatment with therapeutic vaccination, DMBG or anti-PD-1 had marginal effects on tumor growth, but lasting regression was achieved with the combination of DMGB and checkpoint inhibition. The findings uncover new insight into immune suppression by MDSCs and reveal a potential therapeutic target to improve immunotherapy against cancer.
“ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC” by Sangeeta Goswami et al
No validated biomarkers exist to predict response to immune checkpoint blockade in metastatic urothelial carcinoma (mUCC). Reasoning that the identification of biomarkers may require interrogation of both tumor mutational status and the immune microenvironment, Sangeeta Goswami et al performed multi-platform immuno-genomic analyses on baseline tumor samples from patients enrolled in clinical trials evaluating both nivolumab monotherapy and nivolumab combined with ipilimumab. Whole-exome sequencing from paired baseline bladder tumor samples and peripheral blood mononuclear cells (PBMCs) revealed ARID1A as the only gene mutation in the discovery cohort that was significantly enriched in responders compared to nonresponders and targeted gene expression analysis via a custom 739-gene NanoString panel identified genes implicated in immune infiltration, including CXCL13, CXCL9, CCL19, and CCL5. Deletion of CXCL13 eliminated response to anti-PD-1 therapy in bladder tumor-bearing mice. In the confirmatory cohorts of patients from CheckMate275 and IMvigor210, higher expression of CXCL13 correlated with longer overall survival. The association between CXCL13 and overall survival was stronger in patients harboring ARID1A mutations in both confirmatory cohorts. Although the findings will need to be validated prospectively, the study suggests that the combination biomarker approach could offer improved predictive power for response to checkpoint blockade.
“Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy” by Maud Mayoux et al
Maud Mayoux and colleagues uncover a new mechanism by which PD-L1 blockade targets dendritic cells (DCs) to relieve T cell suppression. Analysis of expression levels for PD-L1 and its two receptors, PD-1 and B7.1, on samples from patients with lung cancer revealed that the abundance of PD-L1 on DCs as determined by specific antibody binding capacity was roughly 20-fold higher than B7.1. In co-culture experiments, B7.1 on DCs had little to no interaction with CD28 in the synapse on T cells—instead, the predominant interaction was a cis interaction of PD-L1 and B7.1 on DCs. Pre-incubating DCs with an anti-PD-L1 monoclonal antibody led to significantly stronger interaction of B7.1 with CD28, in both a Tag-Lite assay-based reporter system of ligands and receptors and in primary cells. Disrupting the PD-L1/B7.1 cis interaction on DCs with an anti-PD-L1 monoclonal antibody enhanced CD28 signaling in T cells above the magnitude induced by a PD-1 blocking antibody. In the clinical setting, a high DC cell signature in pretreatment tumor specimens from patients with renal cell carcinoma enrolled into a phase I study (NCT01375842) of anti-PD-L1 atezolizumab was associated with improved overall survival (OS). Similarly, a roughly 8-month OS benefit was seen for the high versus low DC signature group in patients with non-small cell lung cancer treated with atezolizumab in the phase II POPLAR trial. The mechanism suggests that DCs are important cellular targets of anti-PD-L1 checkpoint blockade through disruption of the PD-L1/B7.1 cis interaction, which allows for CD28 costimulation and subsequent antitumor T cell immunity.
“ILC2s Amplify PD-1 Blockade by Activating Tissue-Specific Cancer Immunity” by John Alec Moral et al
Group 2 innate lymphoid cells (ILC2s) are found in cancers, but their roles in cancer immunity and immunotherapy are unclear. John Alec Moral and colleagues analyzed tumor-infiltrating lymphocytes in unselected primary human pancreatic ductal adenocacrinomas (PDACs) and found that ILC2s were specifically enriched in immunologically ‘hot’ tumors in rare long-term PDAC survivors. Longer survival was also associated with higher bulk RNA expression of the ILC2-activating cytokine IL33. ILC2s phenotypically similar to those in human PDACs were detected in both the autochthonous mutant Kras- and p53-driven KPC mouse model and an orthotopic mouse model of PDAC. In both models, IL33 was the most highly expressed ILC-activating cytokine. Loss of IL33 led to tissue-dependent effects, where growth was accelerated for pancreatic tumors, but no change in growth rate occurred for subcutaneously implanted tumors. No differences in tumor histology, collagen, and fibroblast content were seen with deletion of IL33. Treatment with recombinant IL33 prevented tumor establishment in mice with orthotopic PDACs and prolonged survival, but had no effects on mice with subcutaneous PDAC. The tissue-specific effects of IL33 depended on CD8+ T cells—70% of mice with intact IL33 rejected orthotopic KPC tumors expressing the CD8+ T cell rejection antigen OVA, whereas 0% IL33-deficient mice did, and 100% of mice rejected subcutaneous KPC-OVA tumors, regardless of IL33. A combination of recombinant IL33 and anti-PD-1 led to expanded ILC2s in tumors and enhanced tumor control compared to anti-PD-1 alone. Even in an aggressive cold PDAC tumor model that that has reduced CD8+ T cell content and a median survival of only 2 weeks, combination treatment with recombinant IL33 and anti-PD-1 reduced tumor volume by over 50% with a nearly 50% improvement in survival. In human patients, nearly 60% PDACs had low frequencies of PD-1+ ILC2s and PD-1+ T cells, with a significant correlation between the two cell types. Expression of IL33 and PD-1 also correlated at the mRNA level. The findings set the stage for activation of ILC2s as an immunotherapeutic strategy to strategy to prime CD8+ T cells in cancers.