OR09: Frameshift mutations in microsatellite unstable colorectal cancers: from immune signature to personalized immunotherapy

Pauline Maby1, 2, Hafid Kora1, Mohamad Hamieh1, 3, David Tougeron1,4, Gabriela Bindea2, Bernhard Mlecnik2, Helen Angell2, 5, Tessa Fredriksen2, Nicolas Elie6, Jérôme Leprince7, Jacques Mauillon8, 9, Florence Le Pessot10, Richard Sesboüé1, Thierry Frebourg1,8, Jérôme Galon2, Jean-Baptiste Latouche1,8

1 – Inserm U1079-IRIB, Normandy Centre for Medical Genomics and Personalized Medicine, Rouen University, Rouen, France. 2 – Inserm U1138, Paris Descartes University, Pierre et Marie Curie University, Paris, France. 3 – The Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 4 – Department of Gastroenterology, Poitiers University Hospital and EA 4331, Poitiers University, Poitiers, France. 5 – AstraZeneca Pharmaceuticals, Cambridge, UK. 6 – Imaging Core Facility, Caen University Hospital, Caen, France. 7 – Inserm U982-IRIB, Cell Imaging Platform of Normandy PRIMACEN, Rouen University, Mont-Saint-Aignan, France. 8 – Department of Genetics, Rouen University Hospital, Rouen, France. 9 – Department of Gastroenterology, Le Havre Hospital, Le Havre, France. 10 – Department of Pathology, Rouen University Hospital, Rouen, France.

Aim

In colorectal cancers with microsatellite instability (MSI-CRCs), overall tumour-infiltrating lymphocyte (TIL) density and survival rate are known to be higher than in microsatellite stable CRCs (MSS-CRCs). However, the clear links between DNA mismatch repair (MMR) machinery deficiency, TIL density and prognosis remain to be established.

Method

Starting from 141 MSI-CRCs, we studied tumour microenvironment by gene expression profiling and immunohistochemistry, tumour frameshift mutations (FSMs) by multiplex PCRs, and tumour-specific autologous T cell responses using artificial antigen presenting cells developed in the laboratory.

Results

MSI-CRCs, compared to MSS-CRCs, expressed more immune-related genes and were infiltrated with more in situ proliferative T cells, functional CD8+ T cells, B cells and macrophages, which correlated with prolonged survival. Moreover, CD8+ TIL density was associated with the total number of FSMs, and was especially higher when a FSM was present in ASTE1, HNF1A or TCF7L2 gene. Finally, starting from peripheral blood of HLA-A2+ MSI-CRC Lynch patients, we could mount in vitro efficient CD8+ T cell responses against neoantigens derived from FSMs present in their tumour.

Conclusion

Altogether, our results allow us to describe, for the first time to our knowledge, the precise immune signature of MSI-CRCs, and pave the way for developing personalized immunotherapy strategies in these cancers.

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