Dataset Information

PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer.

ABSTRACT: The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1-dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.

SUBMITTER: Goh PK

PROVIDER: S-EPMC8865802 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer.

Goh Pei Kee PK Wiede Florian F Zeissig Mara N MN Britt Kara L KL Liang Shuwei S Molloy Tim T Goode Nathan N Xu Rachel R Loi Sherene S Muller Mathias M Humbert Patrick O PO McLean Catriona C Tiganis Tony T

Science advances 20220223 8

The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low <i>PTPN2</i> associated with improved survival. PTPN2 deletion in murine ma ...[more]

PMID: 35196085

Similar Datasets

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.

Dataset Information

PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer.

Publications

PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets