Submitter Withdrawn 34th Lorne Cancer Conference 2022

PTPN2 elicits cell autonomous and non-cell autonomous effects on anti-tumour immunity in triple negative breast cancer (#256)

Mara Zeissig 1 2 3 , Pei Goh 1 2 3 , Florian Wiede 1 2 3 , Shuwei Liang 1 2 3 , Kara Britt 3 , Nathan Godde 4 , Rachel Xu 1 2 3 , Sherene Loi 3 , Mathias Muller 5 , Patrick Humbert 4 , Catriona McLean 6 , Tony Tiganis 1 2 3
  1. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Department of Biochemistry & Molecular Biology, Monash University, Clayton, VIC, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  5. University of Veterinary Medicine Vienna, Vienna, Austria
  6. Anatomical Pathology, Alfred Hospital, Prahan, VIC, Australia

Introduction: Protein tyrosine phosphatase N2 (PTPN2) is a tumour-suppressor that is absent in a large proportion of triple negative breast cancers (TNBCs). Paradoxically, previous studies have shown that the deletion of PTPN2 in melanoma tumours facilitates T cell recruitment and anti-tumour immunity. Moreover, we have previously shown that the deletion of PTPN2 in T cells markedly enhances anti-tumour immunity by promoting T cell activation and overcoming exhaustion. Here we explored the therapeutic potential of targeting PTPN2 in both tumour cells and T cells to elicit a superior anti-tumour response.

Methods/Results: PTPN2 deficiency in human TNBC was associated with infiltrating T cells and increased expression of PD-L1, the ligand for the PD-1 immune checkpoint, as assessed by immunohistochemistry. Consistent with this, the deletion of PTPN2 in syngeneic murine models of TNBC increased STAT-1-dependent CXCL9/10 expression to recruit T cells and repress tumour growth. The repression in tumour growth by PTPN2 deletion was attributable to lymphocyte recruitment, with no decrease in tumour burden observed compared with controls when PTPN2-deficient tumours were implanted in immunocompromised Rag1-/- mice that lack T and natural killer cells. To determine if deletion of PTPN2 in tumour cells sensitised tumours to immunotherapy, we treated C57BL/6 mice bearing TNBC tumours with anti-PD-1 therapy. The enhanced STAT-1 signalling with PTPN2 deficiency increased PD-L1 expression and subsequently improved the efficacy of PD-1 blockade. Furthermore, the combined deletion of PTPN2 in tumour and T cells facilitated both T cell recruitment and activation, resulting in completely ablated tumour growth.

Conclusion: Our studies demonstrate that PTPN2 deficiency in tumour cells drives STAT-1 signalling and thereby T cell recruitment, PD-L1 expression and enhances the response to immunotherapy. Moreover, the combinatorial targeting of PTPN2 in tumour and T cells can yield added benefit by alleviating inhibitory constraints on recruited or pre-existing T cells to combat TNBC.