Ramamoorthi et al. demonstrated that disseminated cancer cells (DCCs) in bone marrow exhibited a different gene expression profile (stemness and EMT) than primary and metastatic tumor cells in breast cancer. Intratumorally delivered cDC1s primed tumor antigen-specific CD4+ Th1 cells, which modestly controlled primary tumor growth, but were able to migrate into distant organs to eradicate DCC-driven metastases. The CD4+ Th1 cytokine IFNγ regulated cancer stemness, EMT, cell cycle, and cholesterol biosynthesis signatures to restrain the tumorigenic potential of DCCs, but failed to eradicate DCC-driven metastases in IFNγ KO mice.
Contributed by Shishir Pant
ABSTRACT: Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen-specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1- T cells, supporting their nonexhaustion stage. Phenotypic characterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor-draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7-CXCR3+ Th1 cells into distant organs further revealed their potential role in eradicating DCC-driven metastasis. The intratumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4- or IFN-_ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-_ production, inhibited various molecular aspects and increased classical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metastasis in patients.
Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast
Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (4) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (5) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (6) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (7) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (8) Small Animal Imaging Laboratory Core, Moffitt Cancer Center, Tampa, Florida. (9) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (10) Department of Pathology, Moffitt Cancer Center, Tampa, Florida. (11) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (12) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (13) Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. (14) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (15) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (16) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (17) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (18) Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida. (19) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida.
