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Lung cancer is the leading cause of cancer-related deaths worldwide and, despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell–specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared to P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting of P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α2β1–NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2+ MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC_22, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α2β1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC. Interactions between Peptostreptococcus anaerobius and host cells promote recruitment and activation of myeloid-derived suppressor cells, leading to anti-PD1 immune checkpoint inhibitor resistance and exacerbated colorectal cancer in mice.

AbstractObjectivesThe aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post‐burn.MethodsFlow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro‐inflammatory and anti‐inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post‐burn were compared to four age‐matched healthy controls.ResultsWhile overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro‐inflammatory mediators throughout the burn recovery, with a 3–6 fold increase of IL‐17 at 1–3 weeks, and NFκβ 9–18 months post‐burn. T‐regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin‐homing T‐regs (CCR4+) and increased inflammatory (CCR6+) at 1‐month post‐burn, to double‐positive cell types (CCR4+CCR6+) elevated in circulation for 18 months post‐burn. Furthermore, Tregs were observed to proportionally express less IL‐10 but increased TNF‐α over 18 months.ConclusionOverall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post‐burn, instead they become highly specialised, inflammatory and skin‐homing. In this patient population, these changes persisted for at least 18 months post‐burn, this ‘immune distraction’ may limit the ability of immune cells to prioritise other threats post‐burn, such as respiratory infections. In this study, we found that circulating immune cells do not increase or decrease over time post‐burn, instead they become highly specialised, inflammatory and skin‐homing. Changes were observed in Th17 cells, γδ T cells, NKT‐like cells, and double‐positive CCR4+ CCR6+ Treg cells. In this paediatric patient population, these changes persisted for at least 18 months post‐burn, and this ‘immune distraction’ may limit the ability of immune cells to prioritise other threats post‐burn, such as respiratory infections.