Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses.

Junko Matsuzaki,Sacha Gnjatic,Protul Shrikant,Takemasa Tsuji,Hiroshi Shiku,Kunle Odunsi,Sachiko Okamoto,Junichi Mineno,Lloyd J Old,Immanuel F Luescher

doi:10.1038/srep14896

Abstract

Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4+ T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients.

Highlights

Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy
We demonstrated that direct tumor recognition by this latter subset requires non-classical MHC class II (MHC-II) antigen-processing pathways such as proteasomal degradation and transporter-associated with antigen-processing mediated peptide transport, that are typically involved in the MHC class I (MHC-I) presentation, and endosomal recycling
Using the same clones used for the comparative mechanistic analysis in our previous report[13], we first tested tumor-recognizing ability of TR-CD4 against several DP4+ cancer cell lines, in the absence of antigen-presenting cells (APCs)

Summary

Introduction

Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. We investigate anti-tumor functions of TR-CD4 and demonstrate that direct cognate interaction between this subset of human CD4+ T helper cells (TR-CD4) and cancer cells efficiently induce growth arrest in cancer cells and potently provide help to cognate tumor antigen-specific CD8+ T cells in an APC-independent fashion, resulting in significant anti-tumor activity both in vitro and in vivo. Our work is unique in showing that human tumor-recognizing CD4+ T cells have an important role in controlling tumor progression These results provide rationale for adoptive T cell therapy trials testing therapeutic efficacy of TR-CD4 alone or in combination with TCR gene-engineered CD8+ T cells

Methods

Results

Conclusion