Induction of antigen‐specific T_H9 immunity accompanied by mast cell activation blocks tumor cell engraftment

Abstract

The engraftment of circulating cancer cells at distal sites represents a key step in the metastatic cascade, yet remains an unexplored target for therapeutic intervention. In this study, we establish that a vaccination strategy yielding an antigen-specific T H 9 response induces long term host surveillance and prevents the engraftment of circulating cancer cells. Specifically, we show that vaccination with a recombinant CEA IgV-like N domain, formulated with the TLR3 ligand poly I:C, elicits a CEA-specific T H 9 response, wherein IL-9 secreting T H cells act in concert with CEA N domain-specific antibodies as well as activated mast cells in preventing tumor cell engraftment. The development of this immune response was dependent on TLR3, since interference with the TLR3-dsRNA complex formation led to a reduction in vaccine-imparted protection and a shift in the resulting immune response toward a T H 2 response. These findings point to the existence of an alternate tumor targeting immune mechanism that can be exploited for the purpose of developing vaccine therapies targeting tumor dissemination and engraftment.Ninety percent of all cancer-related deaths are associated with the occurrence of metastases, 1-3 with the majority of patients with advanced metastatic cancer given palliative care in the absence of useful curative strategies. Thus, a vaccine strategy designed to induce long term host surveillance to prevent or delay the engraftment of circulating cancer cells, and/or the expansion of micrometastases, would provide an ideal therapy for controlling or limiting relapse in cancer patients.

Serum‐derived carcinoembryonic antigen (CEA) activates fibroblasts to induce a local re‐modeling of the extracellular matrix that favors the engraftment of CEA‐expressing tumor cells

“…An understanding of molecular determinants driving the progression of cancer to a metastatic stage remains limited, thus outlining the complexity of events leading to tumor implantation and the formation of micrometastases. Components responsible for intercellular and cell‐matrix adhesion events involving tumor cells have been shown to serve an important role in the formation as well as expansion of metastatic foci . Currently, few tumor‐derived soluble factors have been identified as causal agents leading to the initiation or the progression of the metastatic cascade.…”

IL-9 and Th9 cells in health and diseases—From tolerance to immunopathology

“…In fact, mast-cell-deficient mice failed to mount effective anti-tumor immunity upon administration of recombinant IL-9. Additionally, inhibition of mast cell activities or depleting mast cells in vivo abrogated tumor-specific Th9 mediated suppression of tumor cell engraftment [72], which further confirmed the role of mast cells in Th9-mediated anti-tumor immunity.…”

TH9 cells in anti-tumor immunity

“…In this setting, the importance of T H 9 cell responses in mediating anti-tumor immunity following vaccination of CEA transgenic mice was shown by demonstrating that IL-9 neutralization prevents the ability of the vaccine to protect mice against a challenge of live colon carcinoma MC38.CEA cells. In this setting, the authors found that treating mice with cromoglycate, which prevents mast cell activity, or with anti-CD117 antibodies, which deplete mast cells, abrogated the anti-cancer efficacy of the vaccine [26]. Overall, these results illustrate that T H 9 cells can enhance mast cell activity through IL-9 secretion, resulting in tumor growth prevention (Fig.…”

“…Altogether, this suggests that in a cancer setting, T H 9 cells are capable of maintaining IL-9- and IL-21-secreting potential, at least long enough to carry out their anti-cancer functions in vivo. These observations may prove relevant in the context of vaccination because a protective T H 9 cell-specific anti-cancer response could be induced through immunization against tumor antigens [26]. Whether vaccination protocols could be optimized to induce stable and specific T H 9 memory anti-tumor cells remains to be determined.…”

“…T H 9 cells are also able to promote the activation of innate cells [22, 23]. Accordingly, IL-9 enhances the anti-tumor activity of mast cells [22, 25, 26]. T H 9 cells enhance the induction of anti-tumor adaptive immune responses.…”