InVivoMAb mouse IgG2b isotype control, unknown specificity

Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compensated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased soluble MAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Conventional type 1 dendritic cells (cDC1s) play a pivotal role in initiating CD8+ T-cell-mediated antitumor immunity, and their intratumoral abundance strongly correlates with immunotherapy efficacy. Here, we demonstrate that orally administered chenodeoxycholic acid (CDCA), a clinically approved metabolic modulator, accumulates in the tumor interstitial fluid (TIF) of tumor-bearing mice as its metabolite taurochenodeoxycholic acid (TCDCA), thereby potentiating the antitumor functions of cDC1s and CD8+ T cells through a gut microbiota-independent mechanism. Mechanistic studies revealed that CDCA mediates this immunomodulatory effect via TGR5 signaling, which enhances cDC1 functionality and subsequently promotes the proliferation and activation of tumor-specific CD8+ T cells. Clinical correlation analysis of human tumor specimens revealed a positive association between Takeda G protein-coupled receptor 5 (TGR5) expression and HLA-A/B/C/E/F/H levels, with elevated TGR5 expression significantly predicting improved overall patient survival. Moreover, CDCA exhibits synergistic antitumor effects when combined with anti-PD-1 immunotherapy and a poly I:C adjuvant, leading to robust tumor growth suppression and enhanced antitumor-immune responses. Overall, our study elucidates a novel immunoregulatory mechanism through which CDCA modulates tumor progression, highlighting CDCA and its bile acid derivatives as promising therapeutic candidates for cancer immunotherapy, providing a potential strategy to overcome resistance in cold tumors by revitalizing the cDC1-CD8+ T-cell axis.

The glioblastoma tumor-immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, protumor macrophages and myeloid cells, and exhausted T cells are all hallmarks of the glioblastoma TIME. In this study, we integrated spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI treatment with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to show that interleukin 6 (IL6) neutralization reprograms the glioblastoma TIME to sensitize mouse glioblastoma allografts to ICI and radiotherapy. Rare human glioblastomas that achieved clinical responses to ICI had lower pretreatment IL6 levels compared with glioblastomas that did not respond to ICI. Diverse immunostimulatory gene therapies suppressed local IL6 levels in mouse glioblastoma allografts, and IL6 from glioblastoma cells and the tumor microenvironment was associated with reduced survival in preclinical models and in patients. IL6 blockade with a neutralizing antibody transiently sensitized mouse glioblastoma allografts to ICI by decreasing immunosuppressive regulatory T cells and increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DC), CD11b+ conventional DCs, and effector CD8+ T cells. IL6 blockade plus ICI sensitized mouse glioblastoma allografts to immunostimulatory ablative radiotherapy. Together, these data suggest that IL6 signaling contributes to ICI resistance in glioblastoma and provides a combination treatment strategy that could be used for patients.

Cancer cells adopt multiple strategies to avoid detection and destruction by the immune system, including exploiting immune checkpoint pathways. B7x (B7-H4, B7S1, or VTCN1), a member of the B7/CD28 family, is frequently expressed in advanced bladder cancer, yet its role in bladder cancer progression and resistance to therapy remains poorly understood. Resistance to PD-1/PD-L1 immune checkpoint blockade immunotherapy significantly limits durable responses, with only 20%-25% of patients with muscle-invasive bladder cancer (MIBC) achieving long-term benefits. Here, we demonstrated that B7x mRNA and protein expression were associated with poor survival outcomes in MIBC patients and mouse models of bladder cancer, respectively. Stable expression of B7x in immune-competent bladder cancer mouse models resulted in enhanced tumor growth and splenomegaly, driven by the exclusion and suppression of tumor-infiltrating antitumor immune cells and the enrichment of pro-tumor and immunosuppressive cells. Consistently, in the IMvigor210 clinical trial, high B7x mRNA expression was correlated with poorer survival in MIBC patients treated with PD-L1 blockade. Notably, combination therapy targeting B7x alongside PD-1/PD-L1 or CTLA-4 blockade reduced tumor burden and overcame resistance to monotherapy. These findings establish B7x as a substantial driver of immune evasion in bladder cancer and highlight its potential as a therapeutic target to improve immune checkpoint blockade efficacy in MIBC.