The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Immunotherapy Biomarkers Section Editor, Ignacio Melero, MD, PhD.
“Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity,” by Mikhail Binnewies et al. Cell 2019 April 18; 177, 556-571.
Effector CD4+ conventional T cells (Tconv) can enhance immunity by liberating dendritic cells (DC) and stimulating pro-inflammatory myeloid cell programs; however, the specific role of conventional DCs (cDC) subsets in eliciting antitumor CD4+ Tconv immunity remains unknown. Through application of single-cell RNA-sequencing to mouse and human myeloid tumor draining lymph node cell populations, Binnewies et al. investigated how differences in tumor microenvironment (TME) might affect the nature of the CD4+ Tconv generated. Results from this study demonstrate that the TME ratio of regulatory T cells to cDC2, a heterogeneous DC population shown to initiate CD4+ Tconv responses, may predict the quality of T cells and associated immune response as well as disease-free survival, further suggesting a role for cDC2 as a biomarker for clinical response to immune checkpoint blockade. This study provides evidence for an important link between cDC2 and CD4 T cell immunity against cancer.
“Crizotinib-induced immunogenic cell death in non-small cell lung cancer,” by Peng Liu et al. Nature Communications 2019 10:1486
Clinical evidence demonstrates that patients with malignant cells lacking features of immunogenic cell death (ICD) have reduced chances of progression-free or overall survival post-chemotherapy. There is also evidence that cisplatin, mitomycin C and other chemotherapeutics are relatively inefficient due to their incapacity to stimulate ICD. Based on evidence suggesting the ability of therapeutic agentsto induce ICD, Liu et al. developed an image-based high throughputscreening method to identify TKIs that might stimulate ICD hallmarks such as autophagy, CALR exposure, and HMGB1. As a surprising result, the ALK and ROS1 targeting agent crizotinib is discovered to be potent ICDinducer . These preclinical results suggest that crizotinib may be advantageously combined with non-ICD inducing chemotherapeutics, as well as with immune checkpoint blockade, to treat NSCLCs that lack ALK or ROS1 genetic rearrangements.
“Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy,” by Elisabeth Perez-Ruiz et al. Nature Letter 2019
Combination immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer, but is also commonly associated with serious immune-related adverse events, necessitating a reduction in the prescribed dose of ipilimumab that is given to patients and often treatment discontinuation. Perez-Ruiz et al. provide pre-clinical evidence that the prophylactic blockade of TNF before the start of combination anti-CTLA-4 and anti-PD-1 therapy prevents immune-related adverse events in murine models, while also moderately augmenting anti-tumor effects from the dual treatment. These results suggest that prophylactic inhibition of TNF may improve the safety of combined ipilimumab and nivolumab immunotherapy, allowing recommended or higher doses of ipilimimumab to be administered, while also offering enhanced anti-tumor efficacy.
“Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma,” by Junfei Zhao et al. Nature Medicine Letters 2019
Anti-PD-1 therapy has demonstrated objective responses in only 8% of patients with recurrent glioblastoma (GBM), a disease with a lower burden of somatic mutations and a more immunosuppressive TME compared to melanoma or NSCLC, where anti-PD-1 therapy has an improved response rate. Given the varied and unpredictable response of patients with GBM to checkpoint blockade, Zhao et al. profiled 66 patients, collecting DNA, RNA, tissue imaging, and clinical data to evaluate the genomic and stromal features associated with clinical outcomes and mechanisms of immunotherapy response. This study identified multiple genomic features related to response to anti-PD-1 therapy in patients with GBM, such as an enrichment for PTEN mutations in tumors of non-responders, suggesting that a sub-group of molecularly defined patients might benefit from this therapy.
“Neoantigen-directed immune escape in lung cancer evolution,” by Rachel Rosenthal et al. Nature 2019 28 March; 567: 479-500
The extent to which an active immune system in untreated early-stage tumors shapes the evolution of the tumor genome and predicts prognosis has not been well distinguished. To better understand the complex interplay between cancer genomic evolution and anti-tumor immunity, Rosenthal et al. integrated genomic, transcriptomic, epigenomic, and pathologic data from a TRACERx 100 cohort to characterize immune infiltration in untreated non-small-cell lung cancer (NSCLC), assessing how this infiltration varies amongand within tumors, and better correlate clinical outcomes with mechanisms of immune-evasion. This study provides evidence that tumor evolution is shaped through immunoediting mechanisms that affect either antigen presentation or neoantigenic mutations themselves, and defined an estimate of the immune-evasion capacity of each tumor, with high immune-evasion capacity being associated with poorer clinical outcome.
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