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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