cancer-primary-healthcare-2019-posters-abstracts

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Volume 2

Journal of Molecular Cancer

Cancer & Primary Healthcare 2019

May 20-21, 2019

Cancer Research & Oncology

Primary Healthcare and Medicare Summit

May 20-21, 2019 | Rome, Italy

Global Meet on

World Congress on

Breast cancer induces tolerogenic state of healthy activated CD4+ lymphocytes,

characterized by reduced PI3K, NFκB, JAK-STAT, Notch, and increased

TGFβpathway activity

Anja van de Stolpe

Philips Research, The Netherlands

Cancer cells can induce a state of immunotolerance, which may be reversed by checkpoint blocker

immunotherapy. Prediction of immunotherapy response remains a challenge. CD4+ lymphocytes are

important for activating the adaptive immune-response, while conversion to immune-suppressed state

impairs the anti-cancer immune-response. Lymphocyte function is controlled by a number of signaling

pathways. We developed tests to quantitatively measure activity of signaling pathways (e.g. Hedgehog, Wnt,

TGFβ, Notch, NFκB, PI3K, JAK-STAT 1/2 and 3, and MAPK) based on Bayesian model inference of activity

from measurements (microarray, qPCR) of mRNA levels of target genes of the transcription factor associated

with the respective signalling pathway[1],[2],[3],[4],[5],[6]. Tests were biologically validated on individual

cell/tissue samples, including immune cells and can be used to characterize functional activity status of

immune cell types. The cellular mechanism underlying breast cancer-induced immunosuppression of CD4+

lymphocytes was investigated.

Method:

Generation of Affymetrix expression microarray data has been described [7]. In brief, dissected

breast cancer tissue fragments from fresh surgical specimens were mechanically dissociated in X-VIVO-20

(SN). Following standard activation, healthy donor CD4+ lymphocytes were incubated with SN. Signaling

pathway activities were measured on Affymetrix data from the CD4+ lymphocyte samples.

Results:

CD4+ lymphocyte activation resulted in induction of PI3K, NFkB, JAK-STAT1/2, JAK-STAT3,

and decrease of TGFβ pathway activities. Incubation with cancer SN only reduced activity of PI3K, NFkB,

JAK-STAT1/2, JAK-STAT3 pathways, while increasing TGFβ pathway activity, in activated lymphocytes,

but. Conclusion: A soluble factor from breast cancer tissue induces immunotolerance in CD4+ lymphocytes,

by increasing TGFβ pathway activity, and reducing activity of effector immune pathways. Investigation

as to the nature of the soluble factor is in progress. Signaling pathway assays can quantitatively measure

the functional immune activity state of CD4+ lymphocytes. Envisioned application is in prediction and

monitoring of immunotherapy response and identification of novel drug targets to reverse cancer-induced

immunosuppression.

J Mol Cancer, Volume 2