Abstract
Background Tissue transglutaminase (TG2), an enzyme overexpressed in cancer cells, promotes metastasis and resistance to chemotherapy. Its distinct effects in cancer versus the host compartments have not been elucidated. Methods Here, by using a TG2 -/- syngeneic ovarian cancer mouse model, we assessed the effects of TG2 deficiency in the host tissues on antitumor immunity and tumor progression. Multicolor flow cytometry was used to phenotype immune cell populations in the peritoneal environment. Cancer cells recovered from malignant ascites were characterized by RNA sequencing, proliferation, and apoptosis assays. Results We observed that host TG2 loss delayed tumor growth and ascites accumulation and caused increased infiltration of CD8 + T cells and decreased numbers of myeloid cells in the peritoneal fluid. Tumor antigen-specific CD8 + T cell cytotoxic responses were enhanced in ascites from TG2 -/- versus TG2 +/+ mice and CD8 + T cell depletion caused accelerated ascites accumulation in TG2 -/- mice. CD8 + T cells from tumor-bearing TG2 -/- mice displayed an effector T cell phenotype, differentiated toward effector memory (T em). Mechanistically, absence of TG2 augmented signals promoting T cell activation, such as increased cytokine-induced STAT1 and attenuated STAT3 phosphorylation in T cells. Additionally, immune-suppressive myeloid cell populations were reduced in the peritoneal milieu of TG2 -/- tumor-bearing mice. In response to the more robust immune response caused by loss of TG2, cancer cells growing intraperitoneally exhibited an interferon-γ(IFN-Î 3) responsive gene signature and underwent apoptosis. In human specimens, stromal, not tumor, TG2 expression correlated indirectly with numbers of tumor-infiltrating lymphocytes. Conclusions Collectively, our data demonstrate decreased tumor burden, increased activation and effector function of T cells, and loss of immunosuppressive signals in the tumor microenvironment of TG2 -/- mice. We propose that TG2 acts as an attenuator of antitumor T cell immunity and is a new immunomodulatory target.
Original language | English (US) |
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Article number | e002682 |
Journal | Journal for immunotherapy of cancer |
Volume | 9 |
Issue number | 9 |
DOIs | |
State | Published - Sep 30 2021 |
Funding
of Veterans Affairs (I01 BX000792-06), the Diana Princess of Wales endowed Professorship from the Robert H. Comprehensive Cancer Center to DM, the Walter S. and Lucienne Driskill Immunotherapy Research fund to BZ, and UEFISCDI (PN-III-P1-1.1-TE-2019-0670) to LS. Flow cytometry analyses were performed in the Northwestern University – Flow Cytometry Core Facility supported by Cancer Center Support Grant NCI CA060553. We are thankful for generous sharing of animals and reagents from Drs Katherine Roby, Gail Johnson, and Siri Iisma and to Bianca Plosnita for the technical support with the StrataQuest software. Competing interests No, there are no competing interests. Patient consent for publication Not required. Funding This research was supported by funding from the US Department
Keywords
- CD8-positive T-lymphocytes
- female
- genital neoplasms
- lymphocyte activation
- lymphocytes
- tumor microenvironment
- tumor-infiltrating
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
- Immunology and Allergy
- Pharmacology
- Immunology