Similar Datasets
Project description:The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We hypothesized that delivering a heterogenous dose of RT would enhance anti-tumor immunity compared to homogenous RT in combination with immune checkpoint blockade (ICI). Using a point source, we delivered a spectrum of dose (~2-32 Gy) to the primary tumor and observed superior systemic immunity in models of metastatic cancer compared to low (2 Gy), moderate (8 Gy), or high (20 Gy) dose homogenous RT. Heterogeneity in RT dose resulted in spatial heterogeneity in gene expression and immune cell infiltration. Moreover, heterogenous RT optimally engaged multiple immune signaling pathways with diverse dose response relationships whereas responses to homogenous RT treatment groups were limited. Single cell RNAseq demonstrated unique enrichment of immune cell populations between each homogenous RT dose group, with several of these dose-dependent changes also represented in the heterogeneously treated tumors, with engagement of both lymphoid and myeloid compartments. This optimized activation of multiple immune mechanisms with distinct dose-dependent profiles within a single tumor may underlie a greater capacity of RT heterogeneity to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose RT.
2024-07-12 | GSE234159 | GEO
Project description:The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We hypothesized that delivering a heterogenous dose of RT would enhance anti-tumor immunity compared to homogenous RT in combination with immune checkpoint blockade (ICI). Using a point source, we delivered a spectrum of dose (~2-32 Gy) to the primary tumor and observed superior systemic immunity in models of metastatic cancer compared to low (2 Gy), moderate (8 Gy), or high (20 Gy) dose homogenous RT. Heterogeneity in RT dose resulted in spatial heterogeneity in gene expression and immune cell infiltration. Moreover, heterogenous RT optimally engaged multiple immune signaling pathways with diverse dose response relationships whereas responses to homogenous RT treatment groups were limited. Single cell RNAseq demonstrated unique enrichment of immune cell populations between each homogenous RT dose group, with several of these dose-dependent changes also represented in the heterogeneously treated tumors, with engagement of both lymphoid and myeloid compartments. This optimized activation of multiple immune mechanisms with distinct dose-dependent profiles within a single tumor may underlie a greater capacity of RT heterogeneity to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose RT.
2024-07-12 | GSE234157 | GEO
Project description:Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade
| PRJNA980214 | ENA
Project description:Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade
| PRJNA980216 | ENA
Project description:Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade
| PRJNA980220 | ENA
Project description:Gut microbiota, specifically gut bacteria, are critical for effective immune checkpoint blockade therapy (ICT) for cancer. The mechanisms by which gut microbiota augment extraintestinal anticancer immune responses, however, are largely unknown. Here, we find that ICT induces the translocation of specific endogenous gut bacteria into secondary lymphoid organs and subcutaneous melanoma tumors. Mechanistically, ICT induces lymph node remodeling and dendritic cell (DC) activation, which facilitates the translocation of a selective subset of gut bacteria to extraintestinal tissues to promote optimal antitumor T cell responses in both the tumor-draining lymph nodes (TDLNs) and the primary tumor. Antibiotic treatment results in decreased gut microbiota translocation into mesenteric lymph nodes (MLNs) and TDLNs, diminished DC and effector CD8+ T cell responses, and attenuated responses to ICT. Our findings illuminate a key mechanism by which gut microbiota promote extraintestinal anticancer immunity.
| S-EPMC10080670 | biostudies-literature
Project description:Despite expression of immunogenic polypeptides, tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, among other mechanisms. What orchestrates these controls is unknown. We report that free C3d, a fragment of the third component of complement, inside tumor cells - or associated with irradiated tumor cells and unattached to antigen - recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells. These properties of C3d appear specific for the tumor and dependent on complement receptor 2, and they incur no obvious systemic toxicity. The heretofore unrecognized properties of free C3d suggest that protein might determine the effectiveness of immune surveillance and that increasing availability of the protein might prove advantageous in the treatment or prevention of cancer and premalignant conditions.
| S-EPMC5414554 | biostudies-literature
Project description:Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint-modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8+ T cells to regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells, and downregulation of the M2 marker CD206 on tumor-associated macrophages. Flt3L improved CD8+ T-cell and dendritic cell infiltration of tumors, but was diminished in efficacy by concomitant Treg expansion. Although intratumoral CDG/checkpoint therapy invokes substantial ulceration at the injection site, reduced CDG dosing can preserve tissue integrity without sacrificing therapeutic benefit. For high-order combinations of T-cell checkpoint antibodies and local myeloid agonists, systemic antibody administration provides the greatest efficacy; however, local administration of CDG and antibody provides substantial systemic benefit while minimizing the potential for immune-related adverse events. Cancer Immunol Res; 5(8); 676-84. ©2017 AACR.
| S-EPMC5547907 | biostudies-literature
Project description:Although it is known that oncolytic viruses can inflame and recruit immune cells to otherwise immunosuppressed tumor microenvironments, the influence of the antiviral immune response on antitumor immunity is less clear across viral platforms and tumor types. CF33 is a recombinant orthopoxvirus backbone effective against colon cancer. We tested derivatives of CF33 with and without immune-checkpoint inhibition (anti-PD-L1) in mouse models of colon cancer. Results showed that the efficacy of CF33 backbone with J2R deletion (single-deleted) against colon cancer is not altered by additional deletion of F14.5L in vitro or in vivo CF33 infection upregulated PD-L1 expression on tumor cells and led to an increased influx of lymphocytes and macrophages in tumors. Also, the levels of active CD8+ (IFNγ+) T cells in the virus-treated tumors were higher than those in control-treated tumors. Furthermore, a combination of CF33 derivatives with anti-PD-L1 resulted in durable tumor regression and long-term survival, resistant to tumor rechallenge. Analysis of immune cells from the treated mice showed that tumor-specific T cell activation occurred more robustly in tumors treated with the virus and that T cells were more strongly activated against the virus than against tumor, in an MHC-I-dependent manner. Our findings warrant further studies on the role of cross-priming of T cells against viral and tumor antigens, in the overall success of viroimmunotherapy.
| S-EPMC7790874 | biostudies-literature
Project description:Emerging evidence suggests a role for radiation in eliciting antitumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced Colony Stimulating Factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking five days following irradiation. These tumour-associated macrophages (TAMs) were skewed toward an immunosuppressive phenotpye. Macrophage depletion via anti-CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti-PD-L1 (aPD-L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti-PD-L1 was required to achieve tumour regression.
| S-SCDT-88789_2_1540197428_jats | biostudies-other