Cancer Dormancy. VII. A Regulatory Role for CD8+ T Cells and IFN-γ in Establishing and Maintaining the Tumor-Dormant State

Abstract

Dormant tumor cells resistant to ablative cancer therapy represent a significant clinical obstacle due to later relapse. Experimentally, the murine B cell lymphoma (BCL1) is used as a model of tumor dormancy in mice vaccinated with the BCL1 Ig. Here, we used this model to explore the cellular mechanisms underlying dormancy. Our previous studies have demonstrated that T cell-mediated immunity is an important component in the regulation of tumor dormancy because Id-immune T cells adoptively transferred into passively immunized SCID mice challenged with BCL1 cells significantly increased the incidence and duration of the dormant state. We have extended these observations and demonstrate that CD8+, but not CD4+, T cells are required for the maintenance of dormancy in BCL1 Ig-immunized BALB/c mice. In parallel studies, the transfer of Id-immune CD8+ cells, but not Id-immune CD4+ cells, conferred significant protection to SCID mice passively immunized with nonprotective levels of polyclonal anti-Id and then challenged with BCL1 cells. Furthermore, the ability of CD8+ T cells to induce a state of dormancy in passively immunized SCID mice was completely abrogated by treatment with neutralizing α-IFN-γ mAbs in vivo. In vitro studies demonstrated that IFN-γ alone or in combination with reagents to cross-link the surface Ig induced both cell cycle arrest and apoptosis in a BCL1 cell line. Collectively, these data demonstrate a role for CD8+ T cells via endogenous production of IFN-γ in collaboration with humoral immunity to both induce and maintain a state of tumor dormancy.

The current paradigm and challenges ahead for the dormancy of disseminated tumor cells

“…Similarly studies on a B-cell lymphoma that establishes dormancy through a vaccination protocol revealed important components on how dormancy could be induced and maintained by CD8+ T cells and IFNγ signaling 6 . Additionally, immune evasion was shown to allow the persistence of dormant leukemic cells in mouse acute myeloid leukemia (AML) through the upregulation of B7-H1 (PD-L1)…”

“…The cancer dormancy field has worked based on three definitions that are not necessarily mutually exclusive and may be complementary. These have led to the working hypothesis that asymptomatic minimal residual disease (MRD) can be defined and explained by three potential scenarios: 1) angiogenic dormancy, an impaired angiogenic response maintaining tumor mass constant in size by balancing proliferation and cell death [1][2][3] ; 2) immune-mediated dormancy, in which proliferative tumor cell populations are constantly trimmed by cytotoxic immune cell responses that also maintain an equilibrium between cell death and proliferation [4][5][6][7][8][9][10][11][12][13] ; and 3) cellular dormancy, in which solitary DTCs or small cell clusters enter a prolonged growth arrest with no increase in cell death 19,[24][25][26][27] .…”

“…In recent years our understanding of metastasis biology and cancer cell dormancy has advanced considerably. Current knowledge of how cancer dormancy proceeds has stemmed from pioneering work on angiogenesis [1][2][3] , immune regulation of equilibrium states and antibody signaling [4][5][6][7][8][9][10][11][12][13] , and on how micro-environmental and signaling mechanisms control cellular dormancy through growth arrest programs 14,15 . Key findings based on this body of work proposed that dormant cells might evade anti-proliferative therapies in a passive manner 16 .…”

T‐box transcription factor 2 mediates antitumor immune response in cutaneous squamous cell carcinoma by regulating the expression of programmed death ligand 1

“…IFNγ is mainly produced by T cells, natural killer (NK) cells and NK T cells, 21 if CD8+ T cells inhibit tumor growth by producing IFNγ, and at the same time, we can also inhibit or downregulate TBX2, IFNγ‐induced downregulation of IRF1 can be promoted, thereby downregulate PD‐L1, resulting in promoting T cell killing. Previous studies have shown that the dormant state of tumors can determine whether IFNγ can suppress dormant cells or edit dormant tumor cells, leading to tumor recurrence 22 . In particular, Ki67‐low indolent cancer cells are vulnerable to immunomodulation that can evade immunotherapy, whereas Ki67‐quiescent dormant cells are not immune‐modulated and thus remain dormant by IFNγ‐producing T cells 23 .…”

Role of myeloid-derived suppressor cells in tumor recurrence

“…Immune-mediated tumor mass dormancy can also control the development and growth of dormant tumor lesions. Thus, the survival and continued growth of primary and secondary tumor foci requires the evasion of the host immune response [ 123 , 124 ]. This mechanism of dormancy is evoked when the rate at which immune-mediated cancer cell cytotoxicity equals cancer cell proliferation, resulting in a malignant mass with a stable size [ 125 ].…”