Presentation on theme: "NOVEL ROLE FOR WNT1 IN LUNG CANCER ESCAPE FROM IMMUNE SURVEILLANCE MECHANISMS. PRELIMINARY RESULTS. DIMITRA KERDIDANI, VASO KARAVANA, SOFIA MAGKOUTA, AGGELIKI."— Presentation transcript:
NOVEL ROLE FOR WNT1 IN LUNG CANCER ESCAPE FROM IMMUNE SURVEILLANCE MECHANISMS. PRELIMINARY RESULTS. DIMITRA KERDIDANI, VASO KARAVANA, SOFIA MAGKOUTA, AGGELIKI MELIGOVA, CHARIS ROUSSOS, SPYROS ZAKYNTHINOS, IOANNIS KALOMENIDIS, MARIA TSOUMAKIDOU. CENTRE FOR APPLIED BIOMEDICAL RESEARCH AND TRAINING “MARIANTHE SIMOS”, FIRST DEPARTMENT OF INTENSIVE CARE MEDICINE, EVAGGELISMOS HOSPITAL
LUNG CANCER BURDEN Lung cancer comprises 14% of cancer diagnoses/30% of cancer deaths. There are more deaths due to lung cancer than breast, prostate, and colon cancers combined. 1.61 million lung cancer diagnoses in 2012 / 1.38 million deaths. For all stages combined, the five-year survival rate is 16% for NSCLC and 6% for SCLC. Jemal A, et al. CA Cancer J Clinic 2010.
THE CANCER IMMUNOEDITING HYPOTHESIS Cancer cells use immune escape mechanisms to evade immunosurveillance. Such immunosuppressive strategies can be: preexisting arise through outgrowth of escape mutants take place during tumor-sculpting actions by the immune system Vesely MD, et al. Annu Rev Immunol; 2011.
THE CANCER IMMUNOEDITING HYPOTHESIS Vesely MD, et al. Annu Rev Immunol; 2011.
THE WNT SIGNALING PATHWAY Sen M, et al. J Immunol; 2008.
KNOWN FUNCTIONS OF THE CANONICAL WNT PATHWAY IN CANCER Canonical Wnt signalling pathway facilitates cancer progression by regulating: tumor growth cell senescence cell death cell differentiation metastasis Polakis P, et al. EMBO; 2012.
Alteration of Wnt pathway components in non–small cell lung cancer Increased expression Decreased expression or inhibition of function Wnt-1 Wnt-2 Wnt-3 Wnt-5a Wnt-11 β -Catenin Frizzled-8 Dishevelled-1 Dishevelled-2 Dishevelled-3 Porcupine TCF-4 Pygopus 2 Wnt-7a AXIN sFRP-1 sFRP-2 sFRP-4 sFRP-5 WIF-1 Dkk-1 Dkk-3 RUNX3 APC CDX2 DACT2 EMX2
WNT1 AND LUNG CANCER PATIENT OUTCOMES Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients. Oncol Rep. 2008;19(1):203–209. Aberrant Wnt1/beta-catenin expression is an independent poor prognostic marker of non-small cell lung cancer after surgery. J Thorac Oncol. 2011;6(4):716–724. Wnt1 overexpression promotes tumor progression in non-small cell lung cancer. Eur J Cancer. 2008;44(17):2680–2688. Wnt1 pathway activation predicts increased risk of tumor recurrence in patients with stage I nonsmall cell lung cancer. Ann Surg. 2013;257(3):548–554.
Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol. 2013;190(12):6126-34. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. 2010;329(5993):849-53. β -Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci U S A. 2015;112(9):2823-8. NOVEL ROLES OF THE CANONICAL WNT PATHWAY IN THE INDUCTION OF IMMUNE TOLERANCE
The Wnt/ β -catenin pathway attenuates experimental allergic airway disease. J Immunol. 2014;193(2):485-95. TLR2-dependent activation of β -catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. J Immunol. 2014;193(8):4203-13. Canonical Wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. J Immunol; 2015 Feb 20. [Epub ahead of print] THE CANONICAL WNT PATHWAY IN IMMUNOLOGICAL DISEASES
NOVEL IMMUNE FUNCTIONS OF THE CANONICAL WNT PATHWAY IN CANCER
Lung cancer cell-derived Wnt1 acts paracrine to suppress anti-tumor T cell responses and is a critical mechanism of lung cancer escape from immune surveillance. HYPOTHESIS
HYPOTHESIS WNT1-INDUCED SUPPRESSION IN THE TUMOR MICROENVIRONMENT Wnt1
Constitutive Wnt1 expression was assessed in Lewis lung carcinoma (LLC) cells by Immunoblot. Wnt1-deficient LLC cells were obtained by stably transfecting cells with Wnt1-silencing shRNA. Control (vector-transfected) and Wnt1-silenced LLC cells (LLC and shLLC) were engrafted in the left lung lobe of syngeneic C57BL/6 mice. T cell responses were assessed on day 10. METHODS
IMMUNOBLOT AND RT-PCR WESTERN BLOT Scrambleshwnt1 wnt1 β -actin
gated on total live cells (sytox-green –ve) Scramble transfected ShWnt1 transfected CD3 + T CELL NUMBERS (% total lung cells) CD3 FSC
CD39 CD73 gated on CD45+CD3+CD4+ T cells gated on CD45+CD3+CD8+ T cells Scramble transfected ShWnt1 transfected ECTONUCLEOTIDASE EXPRESSION (% lung T cells)
IFN- γ IL-10 Scramble transfected ShWnt1 transfected EXPRESSION OF IL-10 and IFN- γ (% lung T cells) gated on CD45+CD3+CD4+ T cells gated on CD45+CD3+CD8+ T cells
CONCLUSION Silencing Wnt1 increases the numbers of T cells that infiltrate lung tumors in vivo lowers expression of the ectonucleotidase CD39 and of the immunosuppressive cytokine IL-10 by intratumoral T cells up-regulates IFN γ expression by intratumoral T cells
Targeting Wnt1 may act simultaneously on both cancer and immune cells at key regulatory points in the cancer-immune network. Targeting this shared signaling pathways in combination with conventional chemotherapy may be a promising strategy for cancer treatment. Sustained targeting of Wnt1 after initial surgery, drug therapy and/or radiotherapy might enhance the ability of the immune system to achieve sterilizing immunity. IMPLICATIONS