Visualizing the course of antigen‐specific CD8 and CD4 T cell responses to a growing tumor

Abstract

Spontaneous tumors frequently express antigens that can be recognized by the immune system but nevertheless manage to evade immune surveillance. To better understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting against a subcutaneously growing tumor, modified to express influenza hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen-specific CD8 T cells was sufficient to protect against challenge with 1x10 6 tumor cells, while larger numbers of T cells rejected established tumors. HA-specific CD4 T cells could not reject tumors on their own but helped rejection by CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded antigenspecific CD8 and CD4 T cells, while a failing anti-tumor response was accompanied by transient expansion followed by rapid elimination of antigen-specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance because of an insufficient number of tumor-specific T cells and antigen overload, resulting in exhaustion of the immune response. In this scenario, adoptive immunotherapy rather than vaccination promises successful treatment.

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

“…These findings have led us to develop tumor-derived antigen-specific vaccine strategies including further exploration of tumor-associated antigens (2) and dendritic cell vaccines for patients with cancer (3, 4). Currently, a potential role of CD4 þ T cells for cancer immunotherapy is being increasingly appreciated (5)(6)(7)(8)(9). Accumulating evidences have shown that tumor-specific CD4 þ T cells eradicate tumors via orchestrating host-derived immune components, especially CD8 þ T cells (7,(10)(11)(12) and natural killer cells (13).…”

“…Currently, a potential role of CD4 þ T cells for cancer immunotherapy is being increasingly appreciated (5)(6)(7)(8)(9). Accumulating evidences have shown that tumor-specific CD4 þ T cells eradicate tumors via orchestrating host-derived immune components, especially CD8 þ T cells (7,(10)(11)(12) and natural killer cells (13). On the basis of these studies, the efficient induction of tumor-specific, multifunctional effector CD4 þ T cells that provoke antitumor function of other immune cells through their CD40 ligand, interleukin (IL)-2, and IFN-g (5,6,11,14) is now recognized as an important aim of antitumor vaccination strategies.…”

“…During tumor progression, tumor-specific T cells result in a dysfunctional or "exhausted" state with impaired effector functions (7,(15)(16)(17). The discordant antitumor T-cell responses in tumor-bearing recipients have been explained by diverse mechanisms, such as the induction of tumor-induced suppressor cells including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC; refs.…”

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

“…In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic viral infections [16][17][18].…”

Antiproliferative Effect of Lactobacillus helveticus and Low Dose Gamma Radiation on Mammary Carcinogenesis

“…Specific CD4 with CD8 cells can reject tumours (Klein et al, 2003). Numerous research studies have focused on probiotics anticancer property exerting resistance to neoplasia and infections (Kato, 2000).…”