The Cancer-Immune Set Point in Oesophageal Cancer

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.

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Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2

Nature Communications ◽

10.1038/s41467-018-06954-z ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 23

Author(s):

Zuqiang Liu ◽

Yan Ge ◽

Haiyan Wang ◽

Congrong Ma ◽

Mathilde Feist ◽

...

Keyword(s):

Vaccinia Virus ◽

Interleukin 2 ◽

Set Point ◽

Immune Set

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Faculty of 1000 evaluation for Elements of cancer immunity and the cancer-immune set point.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.727215077.793529632 ◽

2017 ◽

Author(s):

Paul Nghiem ◽

Aric Colunga

Keyword(s):

Set Point ◽

Cancer Immunity ◽

Immune Set

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Challenging Your Set Point

PsycEXTRA Dataset ◽

10.1037/e324022004-002 ◽

1998 ◽

Author(s):

Keyword(s):

Set Point

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The blirt and the boomerang: Reactions to set-point violations among verbal inhibitors and disinhibitors

PsycEXTRA Dataset ◽

10.1037/e633942013-085 ◽

2005 ◽

Author(s):

Bill Swann ◽

Pranj Mehta

Keyword(s):

Set Point

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18F-Deoxyglucose PET for the staging of oesophageal cancer

Nuklearmedizin ◽

10.1055/s-0038-1625303 ◽

2003 ◽

Vol 42 (03) ◽

pp. 90-93 ◽

Cited By ~ 9

Author(s):

N. Döbert ◽

O. Rieker ◽

W. Kneist ◽

St. Mose ◽

A. Teising ◽

...

Keyword(s):

Oesophageal Cancer ◽

Squamous Cell ◽

Distal Part ◽

Standard Uptake Value ◽

Squamous Cell Carcinomas ◽

Tumour Grading ◽

Positron Emission ◽

Group A ◽

The Mean ◽

Drop Outs

SummaryAim: Evaluation of the influence of histopathologic sub-types and grading of primaries of oesophageal cancer, relative to their size and location, on the uptake of 18F-deoxyglucose (FDG) as measured by positron emission tomography (PET). Methods: 50 consecutive patients were evaluated. There were four drop-outs due to previous surgical and/or chemotherapeutical treatments and thus in 46 patients (28 squamous cell carcinomas and 18 adenocarcinomas) a pretherapeutic PET evalution of the primary including a standard uptake value (SUV) was obtained. In 42 cases data on tumour grading were available also. Results: Squamous cell carcinomas (SCC) were in 7/13/8 cases located in the proximal, medial and distal part of the oesophagus, respectively the grading was Gx in 3, G 2 in 12, G2-3 in 7, and G3 in 6 cases. The SUVmax showed a mean of 6.5 ± 2.8 (range 1.7-13.5). Adenocarcinomas (ACA) were located in the medial oesophagus in two cases and otherwise in its distal parts. Grading was Gx in one, G2 in 4, G2-3 in 3, G3 in 3, G3-4 in 3, and G4 in one case. The mean SUVmax was 5.2 ± 3.2 (range 1-13.6) and this was not significantly different from the SCC. Concerning the tumour grading there was a slight, statistically not relevant trend towards higher SUVmax in more dedifferentiated cancer. Discussion: SCC and ACA of the oesophagus show no relevant differences in the FDG-uptake. While there was a significant variability of tumour uptake in the overall study group, a correlation of SUV and tumour grading was not found.

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