Systemic Immunity Is Required for Effective Cancer Immunotherapy

Matthew H. Spitzer, Yaron Carmi, Nathan E. Reticker-Flynn, Serena S. Kwek, Deepthi Madhireddy, Maria M. Martins, Pier Federico Gherardini, Tyler R. Prestwood, Jonathan Chabon, Sean C. Bendall, Lawrence Fong, Garry P. Nolan, Edgar G. Engleman

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.