Dataset Information

The Cancer-Immune Set Point in Oesophageal Cancer.

ABSTRACT: Immunotherapy has achieved long-term disease control in a proportion of cancer patients, but determinants of clinical benefit remain unclear. A greater understanding of antitumor immunity on an individual basis is needed to facilitate a precision oncology approach. A conceptual framework called the "cancer-immune set point" has been proposed to describe the equilibrium between factors that promote or suppress anticancer immunity and can serve as a basis to understand the variability in clinical response to immune checkpoint blockade. Oesophageal cancer has a high mutational burden, develops from pre-existing chronic inflammatory lesions and is therefore anticipated to be sensitive to immune checkpoint inhibition. However, both tumour- and patient-specific factors including the immune microenvironment, the microbiome, obesity, and host genetics contribute to an immune set point that confers a lower-than-expected response to checkpoint blockade. Immunotherapy is therefore currently confined to latter lines of treatment of advanced disease, with no reliable predictive biomarker of response. In this review, we examine oesophageal cancer in the context of the cancer-immune set point, discuss factors that contribute to response to immunotherapeutic intervention, and propose areas requiring further investigation to improve treatment response.

SUBMITTER: Power R

PROVIDER: S-EPMC7287212 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Cancer-Immune Set Point in Oesophageal Cancer.

Power Robert R Lowery Maeve A MA Reynolds John V JV Dunne Margaret R MR

Frontiers in oncology 20200604

Immunotherapy has achieved long-term disease control in a proportion of cancer patients, but determinants of clinical benefit remain unclear. A greater understanding of antitumor immunity on an individual basis is needed to facilitate a precision oncology approach. A conceptual framework called the "cancer-immune set point" has been proposed to describe the equilibrium between factors that promote or suppress anticancer immunity and can serve as a basis to understand the variability in clinical ...[more]

PMID: 32582553

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Project description:BackgroundIndoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified.MethodsWe utilized a small-molecule radiotracer, 11C-l-1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed 11C-l-1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied 11C-l-1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4.Results11C-l-1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of 11C-l-1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, 11C-l-1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point.ConclusionsPET imaging of IDO1 with 11C-l-1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient's individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.

Dataset Information

The Cancer-Immune Set Point in Oesophageal Cancer.

Publications

The Cancer-Immune Set Point in Oesophageal Cancer.

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