Antitumor CD4+ T Helper 1 Cells Target and Control the Outgrowth of Disseminated Cancer Cells

Abstract

Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen–specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1– T cells, supporting their nonexhaustion stage. Phenotypic char- acterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor- draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7– CXCR3+ Th1 cells into distant organs further revealed their po- tential role in eradicating DCC-driven metastasis. The intra- tumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4 or IFN-γ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-γ pro- duction, inhibited various molecular aspects and increased clas- sical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metas- tasis in patients.