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 Clinical/Translational Cancer Immunotherapy Section Co-Editor, Douglas G. McNeel, MD, PhD.
“Inhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer” by Edith Borcoman et al.
Immune checkpoint inhibitors only induce anti-tumor responses in a subset of patients. Borcoman et al. attempt to identify factors which influence patient response in the tumor microenvironment. Because checkpoint inhibitors function through the activation of T-cells, the study classifies tumors according to genetic signatures of T-cell infiltration and inflammation. In muscle-invasive bladder cancer, low T-cell infiltration is associated with mutations which increase activity in the PI3K signaling pathway. In follow-up experiments in a humanized mouse model system, chemical inhibition of the PI3K pathway resulted in a reduction in tumor growth, increased T-cell infiltration of tumors, and enhanced response to checkpoint inhibitor therapy. These results suggest that tumor susceptibility to checkpoint inhibitor therapy is influenced by the level of T-cell infiltration, and that individual signaling pathways may modulate T-cell infiltration in a tumor type-dependent manner.
“Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor” by Leyuan Ma et al.
T-cells with chimeric antigen receptors (CAR-T cells) have shown efficacy in the treatment of hematologic malignancies, but lack effectiveness against solid tumors. To enhance the anti-tumor effect of CAR-T cell therapy, Ma et al. modified a previously designed system to target vaccines to lymph nodes through binding to albumin, enabling direct entry to the membranes of antigen-presenting cells. In mice, the use of this vaccination system in conjunction with CAR-T cell infusion resulted in expansion of the CAR-T cell population, increased immune infiltration of tumors, reduced tumor growth, and enhanced survival compared to CAR-T cell infusion alone. It was also demonstrated that CAR-T cells expressing 3rd-generation or bispecific antigen receptors also benefit from vaccination. This new vaccination technology could be developed to enhance CAR-T therapy effectiveness and enable the treatment of solid tumors using CAR-T.
“Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory” by Mauro Poggio et al.
PD-L1 displayed on the surface of tumor cells can suppress T-cell activity against those tumor cells; the use of α-PD-L1 checkpoint inhibitors can remove this suppression, increasing antitumor T-cell responses. Tumor which typically express low surface levels of PD-L1, such as prostate cancer, might be expected to respond to α-PD-L1 blockade; however, prostate cancer is only rarely responsive to this therapy. In this study, Poggio et al. determine that prostate cancer cell lines express a significant amount of PD-L1 in secreted exosomes, rather than displaying PD-L1 on the surface. PD-L1 exosomes impaired Raji B-cell activation in vitro. After developing exosome-deficient and PD-L1-deficient tumor cell lines using CRISPR/Cas9 gene deletions, a mouse model showed that tumor cells unable to express PD-L1-containing exosomes were impaired in their ability to form tumors, and that T-cell activity was enhanced in the absence of PD-L1-containing exosomes. These results indicate that exosomal PD-L1 expression can suppress T-cell antitumor activity independently of PD-L1 surface expression.
“PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance” by Vivek Verma et al.
A current area of cancer therapy development is the combination of cancer vaccines with checkpoint inhibitors. Due to a lack of data on the effect of sequencing on this combinatorial therapy, Verma et al. administer α-PD-1 blockade and vaccination to a mouse model either simultaneously or sequentially, giving α-PD-1 therapy before vaccination. Simultaneous administration of these therapies resulted in higher numbers of CD8+ T-cells. Administering α-PD-1 therapy first, on the other hand, impaired CD8 T-cell expansion, increased CD8 T-cell apoptosis, and reduced T-cell activation in the tumor microenvironment. A population of PD-1+CD38hiCD8+ T-cells was identified in the sequential condition, which has been previously demonstrated to impair antigen response and effector functions. Examination of tumor biopsies showed that elevated numbers of PD-1+CD38hiCD8+ cells were associated with failure of α-PD-1 treatment, and that this cell population could serve as a predictive biomarker for α-PD-1 therapy success. The study concludes that the sequence of α-PD-1 and cancer vaccination therapies is important, and that suboptimal priming of CD8 T-cells may result in treatment failure.
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