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.