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Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

ABSTRACT: Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

PROVIDER: PRJNA980214 | ENA |

REPOSITORIES: ENA

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Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

Project description:Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

| PRJNA980216 | ENA

Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

Project description:Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

| PRJNA980220 | ENA

Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

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

Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

2024-07-12 | GSE234157 | GEO

Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-07-12 | GSE234161 | GEO

Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

Project description:Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

| PRJNA1128647 | ENA

Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer

Project description:Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells are required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an anti-tumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the theraputical potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.

2024-07-07 | GSE270858 | GEO

Targeting CD36-PPARβ signaling-mediated metabolic adaptation in intratumoral Tregs primes tumors for PD-1 blockade

Project description:Though high frequency of Tregs in tumor obstructs anti-tumor immune responses, systemic depletion of Tregs caused severe autoimmune disease in mice model. Therefore, specifically targeting intratumoral Tregs is direly needed to fight against tumor. Our study provides a novel approach to target intratumoral Tregs to enhance anti-tumor immunotherapy.

2020-03-01 | GSE139325 | GEO

Targeting CD36-PPARβ signaling-mediated metabolic adaptation in intratumoral Tregs primes tumors for PD-1 blockade

Project description:Targeting CD36-PPARβ signaling-mediated metabolic adaptation in intratumoral Tregs primes tumors for PD-1 blockade

| PRJNA579319 | ENA

Cancer cells impair monocyte-mediated intratumoral T cell stimulation [YUMM3.3]

Project description:The tumor microenvironment (TME) is programmed by cancer cells and critically influences antitumor immune responses. Within the TME, CD8+ T cells undergo full effector differentiation and acquire cytotoxic antitumor functions in specialized niches. While interactions with conventional type-1 dendritic cells (cDC1s) have been implicated in this proces, underlying cellular players and molecular mechanisms remain incompletely understood. Here, we show that inflammatory monocytes can adopt a critical role in intratumoral T cell stimulation. They express Cxcl9, Cxcl10 and Il15, but as opposed to cDC1s that cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I (pMHCI) complexes from tumor cells through “cross-dressing”. Hyperactivation of MAPK signaling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) and inducing the secretion of prostaglandin E2 (PGE2), impairing the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I production and blocking PGE2 secretion restores this process and thereby re-sensitizes tumors to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signaling disrupts T cell responses via counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

2024-09-27 | GSE241749 | GEO

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