Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming

Abstract

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ + CD4-CD8-NK1.1innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infi ltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17 + cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4 + and CD8 + T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumorassociated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy. See related commentary by Banerjee et al., p. 1164.

Targeting the interleukin-17 immune axis for cancer immunotherapy

“…Ablation of the microbiome with antibiotics reduces cancer growth in an IL-17-dependent fashion, which supports the protumoral role of bacteria and IL-17 in the early stages of oncogenesis (Sethi et al, 2019). Moreover, microbial stimuli have been shown to program the immunosuppressive phenotype of many innate and adaptive immune cells, including γδ T cells, Th17 T cells, and the recently described IL-17-producing innate αβ T cells (Hundeyin et al, 2019). Consequently, modulation of the microbiome with concurrent immune-checkpoint blockade may alter IL-17 production and open further opportunities for anti-IL-17-based therapy (Onishi and Gaffen, 2010).…”

Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy

“…CCL5 recruits CCR5-expressing TAMs [ 40 , 41 ]. T cells participate in the anti-tumor immune responses, in part through CCR5-dependent regulation of macrophage differentiation [ 42 ]. The recruitment of immune cells, including tumor-infiltrating lymphocytes (TILs), MDSCs, tumor-associated macrophages (TAMs), innate lymphoid cells (ILCs), Tregs [ 43 ], mesenchymal stem cells (MSCs), and immature dendritic cells (DCs), contributes to tumor-induced immunosuppression [ 44 ].…”

Biology and therapeutic targeting of tumour‐associated macrophages

“…In the latter model, TAMs were shown to produce IL-1β, which prompted γδ T cells to secrete IL-17; in turn, IL-17 orchestrated a pro-metastatic response mediated by neutrophils [103]. Other unconventional T cells, such as IL-17 + CD4 − / CD8 − innate TCRαβ T cells (iαβT), were found recently to influence PDAC progression in concert with TAMs [104]. However, contrary to γδ T cells, IL-17 + iαβT cells enhanced anti-tumoural CD4 + and CD8 + T cells and limited PDAC progression through a mechanism involving CCL5 production and immunostimulatory CCR5 + TAM programming.…”