Systemic Immunity Is Required for Effective Cancer Immunotherapy

Abstract

Summary 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.

Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma

“…Immunotherapies that elicit or augment T cell responses to shared neoantigens derived from driver mutations are especially attractive because they allow treatment of multiple patients and should reduce antigen-negative escape variants. Most studies have focused on neoantigen-reactive CD8 + T cells; however, recent work in murine models has highlighted the importance of local and systemic CD4 + T cells in tumor rejection (24,25). Indeed, the adoptive transfer of CD4 + T cells specific for a non-driver neoantigen induced a clinical response in a single patient with cholangiocarcinoma (26).…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…CAR-T and NK cell therapy has been evaluated in hematological malignancies in clinical trials and in approved clinical applications (12) and is also being translated into solid cancers (13). This strategy will not only provide systemic immunity that is required for effective cancer immunotherapy (14), but may also increase local infiltration of T and NK cells in tumor microenvironment. In line with this idea, a recent review summarized the most recent clinical results on the use of checkpoint inhibitors and CAR-T cells in multiple myeloma (15).…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…Magnetic resonance imaging (MRI) based biomarkers of response to immunotherapy have been recently proposed [212] . Systemic immune response coordinated across tissues has been observed to be essential to tumor rejection [213] . The fraction of tumor-infiltrating partially exhausted cytotoxic T lymphocytes (peCTLs) correlates with response to anti-PD-1 monotherapy, with a low fraction indicating the use of combination checkpoint blockade therapy [214] .…”