Early Events Antigen Presentation CTL Activation and Migration

Tumor cell components are digested by immature dendritic cells (DC) at the tumor site, followed by migration of DC to lymphoid tissues while processing the digested debris. Antigen presentation in conjunction with MHC class I and class II, and initial priming of T cells happens in the lymphoid tissue [15-17]. During their transfer from tumor to lymph nodes (LN), dendritic cells mature and express costimulatory molecules that support the transition of antigen-inexperienced naïve T cells into activated cells. Among these, ligation of CD28 by co-stimulatory molecules B7.1 and B7.2 is required for clonal expansion and proliferation of naïve T cells [18]. Once activated, other ligands, including CD40L and 4-1BB, are over-expressed, and pair with their counterparts on APC to sustain the development of a CTL response [19]. In the absence of co stimulation, TCR binding to its peptide will fail to activate the cell and lead to a state of anergy [20].

Tumor cells create an unfavorable milieu for DC activation. Production of pros-taglandinE2 by tumors induces over expression of indoleamine 2,3-dioxygenase (IDO) protein in DC and significant expression of cell-surface and soluble CD25 protein [21]. As a consequence, T-cell proliferation and clonal expansion are significantly inhibited [22]. Supplying the host with DC from an external source can initiate an antitumor response, but the tolerizing environment created by the tumor will still exert a suppressive effects on T cells [23].

Presentation of tumor antigen is not the mandate of antigen presenting cells only. Cancer cells can present antigens independently. Intact processing machinery and antigen presentation in the MHC class I context is often preserved [24]. There is no need for APC to cross-present digested tumor to evoke CD8+ T cell responses. Direct contact with the tumor suffices [25]. Loss of MHC expression by tumor cells occurs, and impacts the course of disease [26], but is not the rule. If the barrier created by the tumor stroma is overcome, naïve T cells can directly be primed at the tumor site [27, 28]. Tumor stromal cells are capable of taking up tumor components and cross presenting them on MHC class II molecules, resulting in tumor destruction via damage to its stroma [29]. T cells themselves may acquire antigen presentation capacities through acquisition of peptide-MHC complexes (pMHC) from APCs and tumor, as will be described below. Intriguingly, such T-APCs can stimulate Ag-specific CD8+ central memory T cells, and elicit antitumor immunity [30].

Prior to recruitment into the tumor, naïve CTLs migrate from peripheral blood to lymph nodes, where they constantly scan APCs for surface peptides. Only one naïve T cell in 104 to 106 is likely to be specific for a particular antigen [31]. Upon encounter with APCs presenting their cognate epitope, naïve CTL stop their scanning path for several days. This period is necessary for the lymphocytes to proliferate and transform to armed effectors.

Activated CTLs leave the lymphoid tissue and home to the tumor. The organ of antigen acquisition by APC influences the final destination of T cell trafficking. For example, through specific expression of ligands and chemokine receptors, T cells imprinted in peripheral lymph nodes migrate to the skin [32], and T cells encountering antigen presented by intestinal DC migrate to the intestine [33]. An inflammatory milieu may enhance T cell homing through vasodilation and upregulation of adhesion molecules and selectins [32, 34].

Once a contact is made, higher levels of CD2 and LFA-1 will enhance CTL capacity to firmly adhere to the tumor cell, and develop strong engagement - the immune synapse - that potentially result in tumor death.

Was this article helpful?

0 0

Post a comment