InVivoPlus anti-mouse PD-1 (CD279)

Interleukin 1 (IL1) plays dual functions in cancer. It promotes cancer-related inflammation and progression but also influences leukocyte functional activation. IL1 receptor 2 (IL1R2) functions as an IL1 decoy receptor, inhibiting IL1 activity. In this study, we investigated the contribution of IL1R2 in tuning IL1-dependent effects in mouse models of cancer, including colorectal cancer, lung cancer, and primary and metastatic transplantable and chemically induced sarcoma. Even though the prominent role of IL1 is protumoral, IL1R2 deficiency was selectively associated with reduced sarcoma growth, whereas it was irrelevant in other preclinical models investigated. IL1R2 deficiency was associated with a massive infiltration of neutrophils in the tumor, neutrophilia, and increased extramedullary emergency granulopoiesis. Neutrophils were crucial for tumor control in IL1R2-deficient mice. Immunophenotypic and transcriptional profiling of sarcoma-infiltrating neutrophils revealed that IL1R2 deficiency was associated with higher expression of activation or maturation markers and gene expression reprogramming, with downregulation of pathways associated with protumoral functions. In patients with sarcoma, the IL1R2 deficiency gene signature correlated with better clinical outcomes. Thus, this study shows that IL1R2 tunes IL1-driven cancer-associated emergency granulopoiesis and neutrophil functional activation to an antitumor mode in sarcomas and reveals the antitumor potential of neutrophils in this tumor.

Bone metastasis is a devastating consequence of lung cancer. However, the key metabolic factors that determine the risk of bone metastasis remain unclear. Here, we show that glucose transporter type 3 (SLC2A3) is notably overexpressed by lung cancer bone metastatic cells and tissues, as a facilitator of lung cancer bone metastasis. Additionally, SLC2A3 promotes glucose metabolism, which promotes tumor cell proliferation and metastasis via lactate-mediated p53 lactylation. Within the tumor microenvironment, cancer cells serve as the primary source of secreted lactate, which induces protumor bone metastasis via osteoclast differentiation and suppresses the antitumor activity of CD8+ T cells. Subsequently, we developed Paris saponin VII, a SLC2A3 inhibitor that effectively suppressed bone metastasis in lung cancer bone metastasis mouse models and patient organoids. Notably, either inhibition of SLC2A3 or lactate limitation improved the tumor response and increased the sensitivity of lung cancer bone metastases to PD-1 treatment. Collectively, our findings highlight that targeting SLC2A3-mediated lactate metabolism, either alone or in combination with PD-1 inhibition, is a potential strategy for treating lung cancer bone metastasis.

Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation1-3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4-9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10-16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (TH17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide-major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.

Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis1 and cross-presenting abilities2, resulting in antigen-specific T cell immunity3 or tolerance4-8. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown. Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation7,11 of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene12 (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells13 in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.