Abstract
Cancer prognosis often correlates with the number of tumor-infiltrating CD8 T cells, but many of these cells recognize pathogens that commonly infect humans. The contribution of pathogen-specific "bystander" CD8 T cells to antitumor immunity remains largely unknown. Inflammatory cytokines are sufficient for memory CD8 T cell activation and gain of effector functions, indicating tumor-derived inflammation could facilitate pathogen-specific CD8 T cells to participate in tumor control. In this study, we show in contrast to tumor-specific CD8 T cells that pathogen-specific primary memory CD8 T cells inside tumor were not able to exert their effector functions and influence tumor progression. However, infection-induced memory CD8 T cells with defined history of repeated Ag encounters (i.e., quaternary memory) showed increased sensitivity to tumor-derived inflammation that resulted in activation, gain of effector functions, and better control of tumor growth. Thus, memory CD8 T cells with heightened ability to recognize environmental inflammatory stimuli can contribute to antitumor immunity in the absence of cognate Ag recognition.