Tumor-Infiltrating Leukocytes Are Required for Anthracycline Efficacy

Chemotherapeutic agents such as anthracyclines stimulate immunogenic cell death, in which dying cancer cells activate antitumor immune responses that further enhance the clinical efficacy of these drugs. ATP release from dying tumor cells and dendritic cell (DC) activity have been implicated in this process, but it is unclear how tumor cell antigens are presented to T cells in response to anthracycline chemotherapy. Ma and colleagues found that treatment of tumor-bearing mice with anthracyclines induced the recruitment of inflammatory CD11b⁺ myeloid cells, including DCs, into the tumor bed. This accumulation of tumor-infiltrating lymphocytes (TIL) was dependent on the presence of ATP specifically within the local tumor microenvironment and on expression of purinergic ATP receptors. In particular, chemotherapy increased the frequency of the CD11b⁺Ly6C^hiLy6G⁻ subset of TILs, which expressed DC markers and contained a population of granulocyte-monocyte progenitor (GMP) cells. Anthracycline treatment induced the expression of monocytic lineage transcription factors and shifted GMP cell differentiation from the default granulocyte pathway toward a CD11c⁺ inflammatory DC-like phenotype; this effect was also dependent on chemotherapy-driven local ATP release from tumor cells and the activity of purinergic receptors. CD11c⁺CD11b⁺Ly6C^hi cells efficiently captured and presented tumor cell antigens to T cells and protected naïve mice against tumor growth following adoptive transfer, suggesting that the antigen-presenting function of these cells is essential for anthracycline-induced antitumor immune responses. In support of this idea, inhibition of CD11c⁺CD11b⁺Ly6C^hi cell accumulation within tumors abrogated the anticancer effect of anthracyclines in 4 distinct murine tumor models, whereas depletion of other DC subsets, macrophages, or neutrophils did not impair the chemotherapy response. These findings identify ATP-dependent inflammatory DC-like TILs as critical mediators of the therapeutic efficacy of anthracycline chemotherapy.

Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 2013;38:729–41.

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