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SummaryEmerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice.

Background Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also has a negative impact on MDSC numbers but the primary mechanism driving this effect has remained unclear. Methods The 4T1 breast cancer mouse model was used in combination with PI-3065 to gain insights into the effect of PI3Kδ inhibition on MDSCs. Results PI-3065 treatment resulted in a concomitant reduction in MDSC expansion and tumour size. However, targeting Tregs independent of PI-3065 was also associated with reduced tumour volume and MDSC numbers. Surgical removal of tumours resulted in a rapid and significant decline in MDSC numbers, whilst ex vivo studies using cells from PI-3065-treated mice demonstrated no direct effect of the inhibitor on MDSC activity. Conclusions Our data suggest that MDSCs are not inhibited directly by PI-3065 treatment but that their reduced recruitment and immunosuppression within the tumour microenvironment is an indirect consequence of PI3Kδ-inhibition-driven tumour control. This indicates that PI3Kδ inhibition drives tumour immunity by breaking down multiple immunosuppressive pathways through both direct mechanisms (on Treg) and indirect mechanisms, secondary to tumour control (on MDSCs).

Burnet proposed in the 1950's that the immune system is engaged in identifying and destroying abnormal cancerous cells. This process, termed immune surveillance, has been at the centre of intense debate for decades. Results using immunodeficient mice lend support to the immune surveillance hypothesis. We surmised that immune surveillance would be hampered by the inhibitory effect of naturally occurring FoxP3+ regulatory T cells, a population of T cells shown to be present at an increased frequency in a variety of human tumours. The carcinogen, methylcholanthrene was injected subcutaneously into mice and the steady development of fibrosarcomas was observed over approximately 200 days. These fibrosarcomas were strikingly infiltrated with FoxP3+ regulatory T cells implying that these cells impinge upon immune-mediated rejection of the tumour. This was confirmed by partial ablation of FoxP3+ regulatory T-cell activity, which resulted in a marked reduction in tumour incidence. The reduction of tumour incidence was ablated in mice that lacked interferon gamma. These data offer strong support for the concept of immune surveillance and indicate that this process is limited by the inhibitory effect of FoxP3+ regulatory T cells.

Sir, Carcinogen-induced tumours in intact mice exhibit a substantial enrichment of CD4+FOXP3+ regulatory T cells (Tregs) (Betts et al, 2007) and many forms of malignant disease are associated with an expansion of circulating Tregs in patients (reviewed in Betts et al, 2006). Galon et al (2006) demonstrated recently that the type, density and location of T cells within colorectal tumours predicted clinical outcome. In contrast, Tregs have been shown to increase with progression of malignant disease and to correlate negatively with prognosis (Curiel et al, 2004; Wolf et al, 2005). Definitive studies need to be performed to establish the relative contribution of the accumulation of Tregs among tumour-infiltrating lymphocytes to prognosis since it is currently unclear if an early accumulation of Tregs into the tumour environment allows disease progression. Future studies should include a retrospective analysis of Treg infiltration of tumours removed from patients to establish whether patients with early disease and a relatively large infiltration of Tregs had a worse prognosis than predicted by conventional histopathological scoring and conversely, whether those with advanced disease but a relatively low infiltration of Treg had a better prognosis than predicted. Evidence collected from mice suggests that depletion of Tregs enhances immunosurveillance of tumours and uncovers new responses to tumour antigens in patients (Curiel et al, 2004; Clarke et al, 2006). Hence, removal of Tregs may represent a component of future strategies to trigger immune-mediated elimination of tumour tissue. Nishikawa et al (2003) demonstrated that vaccination with self-antigen expanded Treg with enhanced FOXP3 expression and suppressive capacity. This highlights the importance of co-depleting Treg not only to boost tumour-specific immune responses but also to suppress expansion of Treg with shared antigen specificity. The optimal vaccination/depletion strategy needs to be established by defining the impact of preoperative chemotherapy and surgery on the development of antitumour immune responses. Surgical removal of malignant disease is likely to remove the bulk of Treg TIL and reduce the production of suppressive signalling networks, which would undoubtedly improve the likelihood of successful antitumour immune responses to clear residual malignant cells. However, the impact of major surgery on the capacity of the immune response needs to be established. It is also important to weigh up the benefit of postoperative immunotherapy and adjuvant chemotherapy. Chemo/radiotherapy might reduce the capacity of the immune system to mount antitumour immunity. In light of conflicting reports describing the ability of certain treatments to deplete Treg efficiently (Attia et al, 2005; Dannull et al, 2005), conventional chemotherapeutic drugs that are proven to deplete Treg might be the best starting point to develop strategies to co-vaccinate and deplete Treg. Tregs have been shown to be highly susceptible to cyclophosphamide (Ghiringhelli et al, 2004) and fludaribine (Beyer et al, 2005) and previous work by North (1982) has indicated that vaccination with tumour antigens might go hand-in-hand with chemotherapy to deplete Treg and promote antitumour immunity.