Immunotherapy-Induced Tumor Eradication Requires Systemic Immunity

Studies of cancer immunotherapies have focused on the local immune response in the tumor microenvironment, which has limited the understanding of global immune dynamics in antitumor immunity. Spitzer, Carmi, Reticker-Flynn, and colleagues used a mass cytometry approach, similar to flow cytometry but using mass tags in place of fluorophores to accurately measure more parameters per cell, to assess immune cell dynamics in mouse models of spontaneous triple-negative breast cancer and melanoma following immunotherapy with tumor-binding antibodies along with dendritic cell adjuvants. During the “priming phase” before tumor rejection, a widespread expansion of immune cells was observed, including enhanced proliferation of multiple types of immune cells in the tumor microenvironment. In contrast, in the “rejection phase” during tumor regression immune cell proliferation was not elevated. However, increased lymphocyte activation and proliferation was observed in secondary lymphoid organs (i.e., lymph nodes and spleen) and peripheral blood throughout the priming and rejection phases, indicating a systemic immune activation. Coadministering FTY720, a drug that inhibits immune cell migration from the secondary lymphoid organs, with immunotherapy resulted in tumor progression, demonstrating that local activation of tumor-infiltrating leukocytes is not sufficient for tumor regression. Moreover, after blocking immune cell egress from secondary lymphoid organs, T cells transferred from secondary lymphoid organs to naïve animals were sufficient to confer protection against tumors. In particular, a population of peripheral activated CD4⁺ T cells induced prolonged tumor protection. Blood from patients with melanoma who responded to immunotherapy was enriched for activated, nonexhausted CD4⁺ T cells, further supporting a role for CD4⁺ T cells in antitumor immunity. In mouse models, combining immunotherapy with tumor-binding antibodies with anti–PD-L1 therapy to limit inhibition of antitumor immune responses resulted in increased antitumor activity. Collectively, these results indicate that a systemic immune response is required for effective immunotherapy, and suggest that therapies to augment the systemic immune response may improve immunotherapy efficacy.

Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, et al. Systemic immunity is required for effective cancer immunotherapy. Cell 2017;168:487–502.e15.

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