The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Case Reports Section Editor, Alfred Zippelius, MD.
“A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma,” by Alexander C. Huang et al. Nature Medicine 2019 Feb 25; 25:454–461
Systemic immunological responses to checkpoint blockade are observed within several weeks post-treatment initiation. The kinetics of immune reinvigoration of CD8 T cells in the tumor and the relationship to clinical response and outcomes remain however unclear. Huang et al. presents a clinical study examining the use of neoadjuvant/adjuvant anti-PD-1 in patients with stage III/IV resectable melanoma. This study provides insights into the mechanisms of PD-1 blockade, specifically identifying a rapid pathological and immunologic response in tumors correlating with disease free survival, as well as further evidence regarding mechanisms of immune failure, immune regulation, and immune escape.
“Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma,” by Hanjie Li et al. Cell 2019 Feb 7; 176(4):775-789.e18.
Reports from recent single-cell RNA sequencing (scRNA-seq)-based studies of tumor-infiltrating immune cell populations in melanoma and other tumors indicate a highly heterogeneous population of immune cell infiltrates which likely play a central role in therapy outcomes. Hanjie et al. combine scRNA-seq with TCR-seq to produce models representative of the transcriptional states of tumor-infiltrating immune cells of 25 melanoma patients of all different stages and undergoing various treatment strategies. Results from this study provide evidence for a pool of dysfunctional CD8T cells likely to potentiate tumor reactivity across patients.
“Neoantigen-directed immune escape in lung cancer evolution,” by Rachel Rosenthal et al. Nature 2019 March 20; 567:479–485
The extent to which an active immune system shapes the genomic evolution of untreated early-stage tumors remains elusive. To better understand the interplay between the cancer genome and anti-tumor immunity in lung cancer, Rosenthal et al. integrated genomic, transcriptomic, epigenomic, and pathologic data from 88 prospectively acquired tumours within the ‘Tracking Non-Small-Cell Lung Cancer Evolution through Therapy’ (TRACERx) 100 cohort to explore how selection pressures from a heterogeneous tumor microenvironment affects tumor evolution through mechanisms of immune escape. Results suggest that the immune microenvironment is not only highly variable between and within patients but can also vary significantly between distinct regions of the same tumor. This highlights the importance of successful immune surveillance and the diversity of immune-evasion mechanisms which should be considered to design successful immunotherapeutic interventions.
“Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy,” by Meike E. W. Logtenberg et al. Nature Medicine 2019 March 4; 25:612-619
CD47 expression enhanced on tumor cells compared to surrounding healthy tissue creates a ‘don’t eat me’ signal on tumor cells by binding to SIRPα expressed on myeloid cells. Preclinical data have demonstrated that targeting of the CD47- SIRPα axis in combination with tumor-opsonizing antibodies leads to increased tumor control. Building on that rationale, Logtenberg et al. investigated whether deletion or inhibition of glutaminyl-peptide cyclotransferase-like protein (QPCTL), a major component of the CD47-SIRPα checkpoint, limits signaling through the CD47-SIRPα axis, subsequently potentiating the ability of macrophages and neutrophils to kill opsonized tumor cells. This study provides a role for QPCTL as a key modifier of the CD47 protein and a regulator of the CD47-SIRPα pathway, and lends support for the clinical development of CD47 anti-tumor antagonists.
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