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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

3505 - Mutations in Interferon Gamma and Antigen Presentation Pathways are frequent in Hiper/Ultra-Mutated (HiMut) Tumors and could be result of Immune-editing processes in HiMut tumors.

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Cytotoxic Therapy;  Cancer Biology

Tumour Site

Presenters

Josep Maria Piulats Rodriguez

Citation

Annals of Oncology (2018) 29 (suppl_8): viii400-viii441. 10.1093/annonc/mdy288

Authors

J.M. Piulats Rodriguez1, S. Garcia-Mulero1, L. Valle2, V. Moreno3, X. Matias-Guiu4, R. Sanz-Pamplona3

Author affiliations

  • 1 Medical Oncology, Institut Catala d'Oncologia (ICO), 08907 - Barcelona/ES
  • 2 Translational Research Laboratory, Institut Catala d'Oncologia (ICO), 08907 - Barcelona/ES
  • 3 Prevención Del Cancer, Institut Catala d'Oncologia (ICO), 08907 - Barcelona/ES
  • 4 Pathology, Hospital de Bellvitge, Barcelona/ES
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Resources

Abstract 3505

Background

Tumors with a phenotype associated with a high mutational load such as POLE-mutated or those showing microsatellite instability (MSI) are more likely to have clinical responses to immune-checkpoints blockade therapy. Indeed, several clinical trials are currently on-going targeting PD-1 in a variety of cancer types. However, some of these patients do not respond to immunotherapy. Recently, mutations in JAK1 and JAK2 has been reported to be responsible for this resistance.

Methods

Here we explore the effect of functional mutations in genes in the interferon gamma (IFG) signaling and antigen presentation (AP) pathway in endometrial, colorectal, and gastric POLE-mutated and MSI tumors extracted from TCGA.

Results

As a result, we have found that POLE-MSI tumors accumulated more mutations in IFG and AP pathways than randomly expected. Using gene expression data, we corroborate that IFN pathway is under-expressed in IGF/AP mutant tumors. MSI IGF/AP mutant tumors over-express T cell receptor pathway probably as a compensatory mechanism. Moreover, when cell infiltration was assessed, these tumors have a tendency to present higher levels of cytotoxic lymphocytes than non-mutated tumors. However, they showed over-expression of pathways related to anti-PD1 resistance such as epithelial to mesenchymal transition or angiogenesis. These results suggest that despite being infiltrated, IGF/AP mutant tumors are able to evade immune surveillance. Regarding survival, although overall these tumors have a very good prognosis, we observed that IGF/AP mutated endometrial tumors showed higher clinical grade than the non-mutated ones.

Conclusions

Based on these results, we show that regardless of cancer type, HiMut tumors with functional mutations in IFG and AP pathways shows a more aggressive phenotype, and present activation of cellular processes that have been related to immune-resistance, probably to evade destruction by a very active T-cell stroma due to the high amount of neoantigens. This phenotype is even more evident in ultra-mutated POLE tumors. Therefore, HiMut tumors could be exploited as a surrogate to understand mechanisms of immune-resistance.

Clinical trial identification

Legal entity responsible for the study

Institut de Recerca Biomédica de Bellvitge (IDIBELL).

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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