Opening and welcome + Keynote Opening session

ESMO Welcome address

Lecture Time
08:30 - 08:40
Speakers
  • Josep Tabernero (Barcelona, ES)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
08:30 - 09:15
Authors
  • Josep Tabernero (Barcelona, ES)
Opening and welcome + Keynote Opening session

TAT 2018 Honorary Award Keynote Address

Lecture Time
08:50 - 09:15
Speakers
  • Jean-Charles Soria (Gaithersburg, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
08:30 - 09:15
Authors
  • Jean-Charles Soria (Gaithersburg, US)
Opening and welcome + Keynote Opening session

TAT 2018 Scientific Welcome address

Lecture Time
08:40 - 08:48
Speakers
  • Giuseppe Giaccone (Washington DC, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
08:30 - 09:15
Authors
  • Giuseppe Giaccone (Washington DC, US)
Opening and welcome + Keynote Opening session

Presentation of the TAT 2018 Honorary Award

Lecture Time
08:48 - 08:50
Speakers
  • Giuseppe Giaccone (Washington DC, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
08:30 - 09:15
Authors
  • Giuseppe Giaccone (Washington DC, US)
Novel immuno targets Educational session

Q&A

Lecture Time
10:30 - 10:45
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Novel immuno targets Educational session

1IN - TREX1 as a gate-keeper of cGAS/STING-mediated activation of interferon type I in cancer cells treated with DNA-damaging agents

Presentation Number
1IN
Lecture Time
09:15 - 09:30
Speakers
  • Sandra Demaria (New York, US)
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Authors
  • Sandra Demaria (New York, US)

Abstract

Background

The presence of DNA in the cytosol during viral infection elicits virus-specific immunity, a process orchestrated by the induction of interferon type I (IFN-I), which recruits and activates dendritic cells (DCs) capable of cross-priming CD8 T cell against viral antigens. Cytosolic double-stranded (ds)DNA is sensed by the cyclic GMP-AMP synthase (cGAS), which produces cGAMP and activates the downstream adaptor stimulator of IFN genes (STING) to induce IFN-I. CD8 T cells are also key anti-tumor effectors and their activation is largely dependent on the same pathways that regulate the activation of virus-specific CD8 T cells. Endogenous DNA accumulates in the cytosol of cells that harbor defects in the DNA damage repair (DDR) machinery, a common feature of neoplastic cells that can be exploited by DNA damaging chemotherapy and ionizing radiation (IR) to mimic a viral infection and activate cGAS/STING pathway in cancer cells.

Methods

Using several mouse and human carcinoma models we have tested in vitro and in vivo the IR doses and fractionation schedules that optimally induce cancer cell-intrinsic IFN-I production and synergize with immune checkpoint blockade (ICB) to elicit abscopal effects (regression of synchronous non-irradiated tumors).

Results

We found that cytosolic IFN-stimulatory dsDNA accumulation is regulated by the single IR dose size, with an optimal window ranging between 4-12 Gy in most human and mouse carcinoma cells tested. Above these doses, upregulation of the DNA exonuclease TREX1 results in clearance of cytosolic dsDNA, abrogating radiation immunogenicity. Fractionation, i.e., repeated (3 times) daily delivery of radiation therapy at doses within this window, amplifies the IFN-I pathway activation, an effect that requires induction of IFNRA. Using genetic tools we demonstrated that IR synergy with ICBs in inducing abscopal effects is completely dependent on the IR induction of cancer cell-intrinsic IFN-I (Vanpouille-Box et al., Nat Commun 2017).

Conclusions

DNA damaging therapy can be used to enhance tumor immunogenicity and overcome resistance to ICBs. Improved understanding of the mechanisms that control IFN-inducing dsDNA by the TREX1 and cGAS/STING axis will lead to more effective combinations treatments for cancer.

Legal entity responsible for the study

N/A

Funding

National Cancer Institute (NCI), USA, R01CA201246.

Disclosure

The author has declared no conflicts of interest.

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Novel immuno targets Educational session

2IN - Targeting IDO1 function in tumor immunotherapy

Presentation Number
2IN
Lecture Time
09:30 - 09:45
Speakers
  • Francesca Fallarino (Perugia, IT)
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Authors
  • Francesca Fallarino (Perugia, IT)

Abstract

Background

Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions.

Methods

We tested more than 500 small compounds, selected by molecular moleculing and IDO1 binding properties by MicroScale Thermophoresis, in a cellular assay with tumor cells transfected with wild-type IDO1 or IDO1 mutants. Interesting compounds were further evaluated in dendritic cells to establish their capacity to modulate IDO1 signaling activity and immunosuppressive properties.

Results

Besides identifying several new potential drugs inhibiting IDO1 catalytic activity, we identified one compound that was clearly capable of potentiating IDO1 signaling activity and few compounds that weakly inhibited the same IDO1 function.

Conclusions

Although our studies have not led to the identification of a potent negative modulator of IDO1 signaling activity yet, the identification of a positive modulator does indicate that the modulation of IDO1 signaling is feasible and therefore further studies may lead to the generation of innvoative drugs, i.e., IDO1 signaling inhibitors, which could be of possible valuable therapeutic use in the immuno-oncology field.

Legal entity responsible for the study

University of Perugia, Perugia, Italy

Funding

European Research Council

Disclosure

All authors have declared no conflicts of interest.

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Novel immuno targets Educational session

3IN - Arginase inhibitors

Presentation Number
3IN
Lecture Time
09:45 - 10:00
Speakers
  • Vincenzo Bronte (Verona, IT)
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Authors
  • Vincenzo Bronte (Verona, IT)
Novel immuno targets Educational session

4IN - CD137

Presentation Number
4IN
Lecture Time
10:00 - 10:15
Speakers
  • Ignacio Melero (Pamplona, ES)
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Authors
  • Ignacio Melero (Pamplona, ES)
Novel immuno targets Educational session

5IN - TIGIT immunotherapy

Presentation Number
5IN
Lecture Time
10:15 - 10:30
Speakers
  • Hassane M. Zarour (Pittsburgh, US)
Session Name
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
09:15 - 10:45
Authors
  • Hassane M. Zarour (Pittsburgh, US)
Novel epigenetic targets Educational session

Introduction

Lecture Time
11:05 - 11:15
Speakers
  • Susan Bates (New York, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
11:05 - 12:45
Authors
  • Susan Bates (New York, US)
Novel epigenetic targets Educational session

Q&A / Panel Discussion

Lecture Time
12:35 - 12:45
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
11:05 - 12:45