Cancer vaccines: Trafficking of tumor-specific T cells to tumor after therapeutic vaccination

Abstract

Cancer vaccines can induce robust activation of tumor-specific CD8(+) T cells that can destroy tumors. Understanding the mechanism by which cancer vaccines work is essential in designing next-generation vaccines with more potent therapeutic activity. We recently reported that short peptides emulsified in poorly biodegradable, Incomplete Freund's Adjuvant (IFA) primed CD8(+) T cells that did not localize to the tumor site but accumulated at the persisting, antigen-rich vaccination site. The vaccination site eventually became a T cell graveyard where T cells responded to chronically released gp100 peptide by releasing cytokines, including interferon-γ (IFN-γ), which in turn upregulated Fas ligand (FasL) on host cells, causing apoptosis of Fas(+) T cells. T cells that escaped apoptosis rapidly became exhausted, memory formation was poor, and therapeutic impact was minimal. Replacing the non-biodegradable IFA-based formulation with water-based, short-lived formulation in the presence of immunostimulatory molecules allowed T cells to traffic to tumors, causing their regression. In this review, we discuss recent advances in immunotherapeutic approaches that could enhance vaccine-primed immune cells fitness and render the tumor microenvironment more accessible for immune cell infiltration.

Keywords: Cancer; Immunotherapy; Inflammation; T cells; Trafficking.

Fig. 1. Fate of CD8⁺ T cells primed by IFA-based vaccine

(1) Naive CD8⁺ T cells travel to antigen-rich and highly inflamed vaccination site and become primed. (2) Effector CD8⁺ T cells respond to persistent antigen presentation by continued expansion and secretion of inflamma tory cytokines (IFN-γ). (3) Activated CD8⁺ T cells up regulate Fas and other inhibitory surface markers including PD-1, LAG-3, Tim-3 and CTLA-4 in response to antigen, IFN-γ and other inflammatory cytokines; these conditions also promote accumulation of host cells expressing PD-L1 and FasL. PD-1/PD-L1 engagement leads to T cell exhaustion; Fas/FasL engagement results in T cell apoptosis. (4) As a result, very few primed T cells reach the tumor.