Dodd, G. | Search bioRxiv

bioRxiv2022

Loss of the adhesion protein Kindlin-1 stimulates tumor clearance via modulation of Tregs

The adhesion protein Kindlin-1 is over-expressed in breast cancer where it has been shown to be associated with metastasis-free survival, however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in a mouse model of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells leads to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs and impairment of their immune-suppressive activities in Kindlin-1 depleted tumors. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of mammary tumorigenesis. Analysis of cytokines secreted from the Met-1 cells identified a significant increase in IL-6 secretion when Kindlin-1 was depleted. Conditioned media from Kindlin-1 depleted cells lead to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6 and depletion of CD25+ Tregs resulted in a reduction of Met-1 tumor growth in mice. Overall, these data identify a novel function for Kindlin-1 in the regulation of anti-tumor immunity through cytokine regulation of Treg number and function.

cancer biology↗

bioRxiv2019

PTPN2 deletion in T cells promotes anti-tumour immunity and CAR T cell efficacy in solid tumours

Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling thereby enhancing both CAR T cell activation and homing to CXCL9/10 expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR T cell therapy against solid tumours.

immunology↗