The Journal for ImmunoTherapy of Cancer (JITC), the official journal of the Society for Immunotherapy of Cancer (SITC), is a leading publication of original research articles, literature reviews, position papers and discussion on all aspects of tumor immunology and cancer immunotherapy–from basic research to clinical application.
To provide JITC readers with a well-rounded view of research in tumor immunology and cancer immunotherapy, JITC editors (view the JITC Editorial Board here) will share a monthly reading list of publications in other journals that have their attention and add value to what readers may find in JITC.
The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Basic Tumor Immunology Deputy Editor, Sjoerd H. van der Burg, PhD.
“Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression” by Samir Devalajara et al.
Retinoic acid (RA) has long been considered to exert anti-tumor effects by promoting differentiation in several types of malignant cells. Samir Devalajara and colleagues provide compelling evidence for a pro-tumor role of RA in the tumor microenvironment. They showed that RA skewed monocyte differentiation toward suppressive tumor-associated macrophages (TAMs) and away from dendritic cells (DCs). Elevated RA in tumor compared to normal mesenchymal tissues was observed in three murine sarcoma models, and TAMs in these mice expressed high levels of RA binding proteins. In vitro differentiation assays and in vivo lineage tracing experiments showed that tumor-derived RA biases monocytes toward TAMs. Microarray analyses revealed that RA exposure downregulated the expression of Irf4, which encodes a transcription factor key for DC differentiation and that IL-13 signaling was correlated with RA production. Genetic ablation of RA production as well as pharmacological blockade both decreased the frequency of TAMs while increasing activation markers on antigen presenting cells and T cell frequencies in mouse models. A unique “RA response score” derived from microarray profiles of RA-treated human monocytes, clustered uniquely within certain sarcoma subtypes in data from The Cancer Genome Atlas and significantly correlated with multiple members of the immunosuppressive transforming growth factor beta and IL-10 signaling pathways. The study adds new nuance to RAs role in tumor progression by demonstrating its capability for myeloid-mediated immune suppression, providing proof of concept for targeting the pathway for immunotherapy.
“Vaccination against non-mutated neoantigens induced in recurrent and future tumors” by Greta Garrido et al.
An ongoing challenge for translating tumor vaccines into the clinic is that the tumors of most patients express too few mutation-derived neoantigens to elicit protective immunity. Furthermore, the neoantigens that will emerge in recurring tumors cannot be predicted based on prior biopsies. To develop a more universal cancer vaccination strategy, Greta Garrido et al. took advantage of induced presentation of class I-restricted epitopes called T cell epitopes associated with impaired peptide processing (TEIPP), occuring due to downregulation of the transporter-associated with antigen processing (TAP). Importantly, TAP downregulation (which is observed in many metastases) leads to the presentation of a common and predictable set of new antigens. In murine and human cell lines, dendritic cells (DCs) pulsed with a CpG oligonucleotide (a potent TLR9 agonist) conjugated to a TAP-specific siRNA were able to prime cognate T cells to develop a cytotoxic response against a specific TEIPP. In mouse models of TAP-knockdown adenocarcinoma, vaccination with the CpG-TAP siRNA was more effective at controlling tumor growth than to vaccination against a mixture of three prototypic mutation-derived neoantigens. Potent tumor inhibition was maintained when vaccinated mice were challenged with TAP-deficient tumor cells as long as 90 days post vaccination. The vaccination strategy also controlled recurrent tumors in a mouse model of pancreatic cancer prevented tumor development in a murine breast cancer model. Inhibition of tumor growth in mice required CD8+ T cells and was correlated with a pro-inflammatory response, characterized by increases in CD8+ and CD4+ T cells, cross-presenting CD103+ DCs, M2 to M1 polarization of macrophages, and ratios of CD8+ cells to myeloid cells, Tregs, and granulocytic MDSCs. No signs of autoimmunity were observed. The strategy could be a promising approach for a universal tumor vaccine for immune-escaped tumors with low TAP expression.
“CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity” by Alvaro Teijeira et al.
Neutrophils undergo a unique form of cell death called NETosis, during which decondensed DNA is explosively projected into the surrounding tissues where it may entrap pathogens. In human B cell lymphomas, NETosis has been correlated with poor prognosis and evidence from animal models has linked the process to metastasis and tumor growth. Alvaro Teijeira et al. use an elegant combination of in vitro culture systems and intravital imaging to demonstrate that tumor-secreted CXCR1 and CXCR2 ligands including IL-8 induce NETosis, and the extruded DNA shields cancer cells from T cell cytotoxicity. In spheroid culture systems as well as in vivo murine models of breast, lung and colorectal cancers, blockade of CXCR1 and CXCR2 virtually abolished NETosis induction by tumor cells. In co-culture experiments with tumor spheroids and IL-8-stimulated neutrophils, NETosis protected cancer cells against cytotoxicity by CD8+ T cells and NK cells. Time-lapse confocal microscopy revealed that CD8+ T cell and NK cell contacts with tumor cells were significantly reduced when extruded DNA was surrounding tumor cells. Intravital microscopy confirmed diminished contacts between CD8+ T cells and NK cells and DNA-surrounded tumor cells in vivo. In a model of lung metastasis, treatment with DNase I as pharmacological inhibition of NETosis significantly reduced the formation of secondary masses—the protective effect of which was not observed in mice lacking T cells and NK cells. Inhibition of NETosis alone did not delay progression of established tumors, but synergized with checkpoint inhibition. The study shows how neutrophils may contribute to immune escape and hints at translational strategies to inhibit NETosis to enhance the efficacy of cancer immunotherapy.
“Peripheral T cell expansion predicts tumor infiltration and clinical response” by Thomas Wu et al.
Recent observations have questioned the model that checkpoint blockade acts on chronically stimulated T cells to reverse a terminally differentiated, exhausted state. In a tour de force of transcriptomics, Thomas Wu and colleagues provide evidence that non-exhausted T cells and T cell clones supplied from the periphery may be key factors in explaining patient variability and clinical benefit from cancer immunotherapy. To comprehensively survey the profiles of various T cell populations in tumors, normal adjacent tissue and peripheral blood, Wu et al. sequenced 330 million mRNA transcripts in 141,623 T cells from 14 treatment-naive patients across four different types of cancer. T cells were grouped into 56,975 distinct clonotypes by matching CDR3 regions, which allowed for the measurement of clonal expansion and lineage tracking across tissues. Strikingly, clones that were highly expanded in blood showed evidence of parallel expansion in tumor and normal adjacent tissue. Cluster analysis and lineage tracking identified revealed that blood-expanded Teff clones had a disproportionate influence on the prevailing clonotypes of Tem and Trm in blood and tumors. In 2 patients, a statistically significant interaction between blood association and exhaustion phenotype was observed, with non-exhausted clones more likely to be blood-associated. Analysis of bulk tumor RNA-seq from 3 randomized phase II trials of the anti-PDL1 antibody atezolizumab revealed that gene signatures characteristic of clonal expansion in both blood and tumor were associated with greater progression-free survival. The results add nuance to our understanding of the mechanisms underlying clinical response to checkpoint inhibition and not only suggest that sampling and identifying expanded clones in blood may assist in characterizing the TCR composition of clinically relevant intratumoural T cells but also bears impact on adoptive cell transfer approaches using tumor-infiltrating T lymphocytes.
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