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IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis due to the lack of therapeutic targets. Although immunotherapy brings survival benefits to patients diagnosed with TNBC, it remains limited and treatment resistance is widespread. Here we demonstrate that IFI35 is highly expressed in tumor tissues and can be induced by Interferon-γ in a time-dependent and concentration-dependent manner in breast cancer cells. In xenograft models, we reveal that IFI35 dramatically increases myeloid-derived suppressor cells infiltration in tumors, along with depletion and anergy of CD8⁺T cells. IFI35 ablation leads to prolonged survival of the mice. Mechanistically, RNA-sequencing reveals that IFI35 promotes CCL2 secretion, resulting in the remodeling of TNBC immune microenvironment. Ablation of IFI35 promotes the infiltration of effector CD8⁺T cells, and thereby sensitizes TNBC to anti-PD-1 immunotherapy. Our data suggest that IFI35 limits antitumor immunity and may be expected to become a new immunotherapy target in TNBC.

SUBMITTER: Xu B

PROVIDER: S-EPMC10907302 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

Xu Baojin B Sun Hefen H Liu Simeng S Liao Li L Song Xiaoqing X Wu Yi Y Hou Yifeng Y Jin Wei W

Oncogene 20240112 10

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis due to the lack of therapeutic targets. Although immunotherapy brings survival benefits to patients diagnosed with TNBC, it remains limited and treatment resistance is widespread. Here we demonstrate that IFI35 is highly expressed in tumor tissues and can be induced by Interferon-γ in a time-dependent and concentration-dependent manner in breast cancer cells. In xenograft models, we reveal th ...[more]

PMID: 38216673

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Project description:IntroductionTriple negative breast cancer (TNBC) is the most aggressive and hard-to-treat subtype of breast cancer, affecting 10-20% of all women diagnosed with breast cancer. Surgery, chemotherapy and hormone/Her2 targeted therapies are the cornerstones of treatment for breast cancer, but women with TNBC do not benefit from these treatments. Although the prognosis is dismal, immunotherapies hold significant promise in TNBC, even in wide spread disease because TNBC is infiltrated with more immune cells. This preclinical study is proposing to optimize an oncolytic virus-infected cell vaccine (ICV) based on a prime-boost vaccination strategy to address this unmet clinical need.MethodsWe used various classes of immunomodulators to improve the immunogenicity of whole tumor cells in the prime vaccine, followed by their infection with oncolytic Vesicular Stomatitis Virus (VSVd51) to deliver the boost vaccine. For in vivo studies, we compared the efficacy of a homologous prime-boost vaccination regimen to a heterologous strategy by treating 4T1 tumor bearing BALB/c mice and further by conducting re-challenge studies to evaluate immune memory responses in surviving mice. Due to the aggressive nature of 4T1 tumor spread (akin to stage IV TNBC in human patients), we also compared early surgical resection of primary tumors versus later surgical resection combined with vaccination.ResultsIn vitro results demonstrated that immunogenic cell death (ICD) markers and pro-inflammatory cytokines were released at the highest levels following treatment of mouse 4T1 TNBC cells with oxaliplatin chemotherapy and influenza vaccine. These ICD inducers also contributed towards higher dendritic cell recruitment and activation. With the top ICD inducers at hand, we observed that treatment of TNBC-bearing mice with the influenza virus-modified prime vaccine followed by VSVd51 infected boost vaccine resulted in the best survival. Furthermore, higher frequencies of both effector and central memory T cells along with a complete absence of recurrent tumors were observed in re-challenged mice. Importantly, early surgical resection combined with prime-boost vaccination led to improved overall survival in mice.ConclusionTaken together, this novel cancer vaccination strategy following early surgical resection could be a promising therapeutic avenue for TNBC patients.

Project description:The Cry1Ac protoxin from Bacillus thuringiensis is a systemic and mucosal adjuvant, able to confer protective immunity in different infection murine models and induce both Th1 and TCD8+ cytotoxic lymphocyte responses, which are required to induce antitumor immunity. The Cry1Ac toxin, despite having not being characterized as an adjuvant, has also proved to be immunogenic and able to activate macrophages. Here, we investigated the potential antitumor adjuvant effect conferred by the Cry1Ac protoxin and Cry1Ac toxin in a triple negative breast cancer (TNBC) murine model. First, we evaluated the ability of Cry1Ac proteins to improve dendritic cell (DC) activation and cellular response through intraperitoneal (i.p.) coadministration with the 4T1 cellular lysate. Mice coadministered with the Cry1Ac protoxin showed an increase in the number and activation of CD11c+MHCII- and CD11c+MHCII+low in the peritoneal cavity and an increase in DC activation (CD11c+MHCII+) in the spleen. Cry1Ac protoxin increased the proliferation of TCD4+ and TCD8+ lymphocytes in the spleen and mesenteric lymph nodes (MLN), while the Cry1Ac toxin only increased the proliferation of TCD4+ and TCD8+ in the MLN. Remarkably, when tested in the in vivo TNBC mouse model, prophylactic immunizations with 4T1 lysates plus the Cry1Ac protoxin protected mice from developing tumors. The antitumor effect conferred by the Cry1Ac protoxin also increased specific cytotoxic T cell responses, and prevented the typical tumor-related decrease of T cells (TCD3+ and TCD4+) as well the increase of myeloid-derived suppressor cells (MDSC) in spleen. Also in the tumor microenvironment of mice coadministered twice with Cry1Ac protoxin immunological improvements were found such as reductions in immunosupressive populations (T regulatory lymphocytes and MDSC) along with increases in macrophages upregulating CD86. These results show a differential antitumor adjuvant capability of Cry1Ac proteins, highlighting the ability of Cry1Ac protoxin to enhance local and systemic tumor immunity in TNBC. Finally, using a therapeutic approach, we evaluated the coadministration of Cry1Ac protoxin with doxorubicin. A significant reduction in tumor volume and lung metastasis was found, with increased intratumoral levels of tumor necrosis factor-α and IL-6 with respect to the vehicle group, further supporting its antitumor applicability.

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IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

Publications

IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

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