Impact of Immunogenic Cell Death and Antigen Spreading on Cancer Vaccine Effectiveness

In lack of full understanding of the needed design principles, the efficacy of current cancer vaccines remains disappointing. This is characterized by poor T-cell infiltration and activation, failure to induce immunogenic cell death (ICD) and subsequent antigen spreading (AS) required to prevent immune escape. While ICD induced by cellular immunity has the potential to drive DC maturation and recruitment, ICD induced by antibodies (Ab) and thus triggering FcγR-dependent mechanisms fail to do so. Thus involved macrophages may even drive loss of essential CTL effector functions, leading to short-lived, non-replenishing, terminally exhausted CTLs. Hence, we hypothesize that cancer vaccines should instead induce ICD and AS through CTLs and/or Abs recruiting DCs, rather than involving macrophages. For proof-of-concept, we use aggressively growing murine tumors tailored to express well characterized model antigens (hCD20, OVA) and immunize with matched viral vaccines. Vaccine-induced immunity is analyzed to identify key mechanisms correlating with AS and anticancer activity. The dependency of ICD on Ab and CTLs is confirmed using FcγR KO mice and depletion of distinct immune cell subsets, respectively. Transcriptomic analysis is used to unveil the relative contributions of Ab- and CTL-mediated ICD to immune cell activation and differentiation and, lastly to AS and sustained tumor control. Reverse translation of these insights may help rationalize design of modern cancer vaccines.