Adoptive chimeric antigen receptor (CAR) T cell therapy has emerged as an exciting new immune-based therapy for hematological malignancies. However, the therapeutic efficacy of CAR T cells in other malignancies, including solid tumours, has been relatively poor.
Our previous studies have defined the role of protein tyrosine phosphatase N2 (PTPN2) in setting TCR signaling thresholds for the maintenance of peripheral T cell tolerance. In particular PTPN2 limits CD8+ T cell responses after the cross-presentation of neo-self-antigens.
Here we report that PTPN2-deficient CD8+ T cells expressing a tumour-specific CAR targeting the HER-2 oncoprotein, which is expressed in many tumours including breast and colon cancers, acquire enhanced cytotoxic activity after contact with tumour antigen and more effectively promote the killing of HER-2-expressing tumour cells. Adoptively transferred PTPN2-deficient central memory HER-2 CAR T cells prevented the growth of HER-2 overexpressing orthotopic tumours. The repression of tumour growth was accompanied by increased CD8+ T cell infiltration into tumours and diminished T cell exhaustion, as assessed by decreased PD-1 and Lag-3 expression. Moreover, the repression of tumour growth by PTPN2-deficient HER-2 CAR T cells was not accompanied by systemic T cell activation and did not result in collateral tissue damage. These studies have defined PTPN2 as a target to enhance the anti-tumour efficacy of CAR T cells in otherwise therapy-resistant solid tumours.