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Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy.

ABSTRACT: Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα^-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα^-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα^-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.

SUBMITTER: Bian Z

PROVIDER: S-EPMC8163884 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy.

Bian Zhen Z Shi Lei L Kidder Koby K Zen Ke K Garnett-Benson Charlie C Liu Yuan Y

Nature communications 20210528 1

Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα<sup>-deficient</sup> macrophages activated by irradiated tumor-released DAMPs exhibit ro ...[more]

PMID: 34050181

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Project description:BackgroundTo date, a growing body of evidence suggests that unfolded protein response (UPR) sensors play a vital role in carcinogenesis. However, it remains unclear whether they are involved in pancreatic ductal adenocarcinoma (PDAC) and how they relate to clinical outcomes. This study aims to investigate the biological function and mechanism of how a novel UPR sensor, CREB3L1 works in PDAC and further evaluate its clinical application prospect.MethodsWe tested UPR signaling including CREB3L1 in Thapsigargin-treated PDAC cells. Subsequently, we defined CREB3L1 expression and further analyzed its expression with clinical characteristics in PDAC. Then, we established gene-modified cells to determine whether CREB3L1 functions in cell proliferation and migration capacity. Besides, we constructed subcutaneously and orthotopically transplanted mice models to verify their progrowing function and pulmonary metastasis models to prove their proinvasion role. What's more, RNAseq, qPCR, Western blotting, immunohistochemistry and multicolor flow cytometry experiments were used to explore the mechanism of how CREB3L1 worked in PDAC. Lastly, CREB3L1 expression correlation with PDAC immunotherapy outcome and immune cell signatures were explored in the patients with advanced PDAC who received PD-1 antibody therapy.ResultsWe first confirmed CREB3L1 could be induced by endoplasmic reticulum stressor and found its aberrant activation was associated with poorer overall survival in PDAC patients indicating the protumor function of the new UPR sensor. Functionally, we confirmed CREB3L1 contributing to PDAC malignant progression including growth and metastasis by multiple in in vitro and in vivo models. Mechanistically, CREB3L1 upregulated COL3A1 and promoted dense stroma formation for facilitating PDAC and knocking down COL3A1 disrupted CREB3L1 protumor function. Furthermore, CREB3L1-induced TAM polarization toward an M2 phenotype and reduced the infiltration of CD8+ T cells. Clinically, CREB3L1 correlated with immune cell signatures as well as immune checkpoint blockade (ICB) treatment response and outcome that CREB3L1aberrant activation indicated poorer efficacy and worse prognosis than the low in PDAC which might empower clinical decision.ConclusionsCollectively, this study revealed CREB3L1 facilitated PDAC progression, shaped an immune exclude tumor microenvironment and distinguished therapy response and outcome of ICB therapy indicating CREB3L1 could be a promising novel molecular target and biomarker for PDAC treatment.

Dataset Information

Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy.

Publications

Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy.

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