40P - Immune pruning of genomic heterogeneity in TNBC

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Breast Cancer
Pathology/Molecular Biology
Presenter Thomas Karn
Authors T. Karn1, T. Jiang2, C. Hatzis2, N. Sänger1, A. El-Balat1, A. Rody3, U. Holtrich1, S. Becker1, G. Bianchini4, L. Pusztai2
  • 1Dept. Of Gynecology And Obstetrics, Johann-Wolfgang Goethe University, 60590 - Frankfurt/DE
  • 2Yale Cancer Center, Yale University, New Haven/US
  • 3Dept. Of Gynecology And Obstetrics, University Hospital Lübeck, Lübeck/DE
  • 4Dept. Of Gynecology And Obstetrics, IRCCS Ospedale San Raffaele, Milan/IT

Abstract

Body

Background: Mechanistic understanding of how immune surveillance shapes the cancer genome is important because it might help selecting patients for immunotherapies and developing more effective immunotherapy strategies. The immunoediting hypothesis of cancer progression suggests, some cancers may be completely eliminated before diagnosis by an antitumor immune response, while most clinically apparent cancers represent states of partially control or escape from immune surveillance. One could hypothesize that extensive lymphocytic infiltration is a consequence of a strong anti-tumor immune response that results in “pruning” of genomic heterogeneity of the cancer by eliminating many immunogenic cell clones, while cancers that have escaped immune surveillance will have low lymphocytic infiltration and evolve towards greater clonal heterogeneity and genomic complexity.

Methods: To test this hypothesis we compared clonal heterogeneity, somatic copy number alterations, mutation and neoantigen load, and distribution of mutations in 119 canonical cancer genes between among TNBC from TCGA stratified by prognosis according to immune gene signatures or by histologically quantified lymphocyte infiltration.

Results: We found a strong inverse relationship between clonal heterogeneity and immune metagene expression (rho= -0.395, P=2e-8). We also observed a strong inverse relationship between immune metagene expression and somatic copy number alteration levels (rho= -0.484, P=2e-10). Moreover, lymphocyte rich TNBC with good prognosis had significantly lower mutation and neoantigen counts than lymphocyte poor TNBC with poor prognosis, but increased frequency of CASP8 mutation (P=0.007). We validated our results using both different immune metagenes and histological quantification of infiltrating immune cells and in an additional independent dataset.

Conclusions: Our data suggest that immune cell rich TNBC is under a strong immune surveillance which continuously eliminates many immunogenic clones resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBC that could derive benefit from immune checkpoint inhibitor therapy.

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