miR-155 Overexpression in OT-1 CD8+ T Cells Improves Anti-Tumor Activity against Low-Affinity Tumor Antigen

Abstract

Therapy by adoptive transfer of ex vivo-expanded tumor-infiltrating or genetically modified T cells may lead to impressive clinical responses. However, there is a need to improve in vivo persistence and functionality of the transferred T cells, in particular, to face the highly immunosuppressive environment of solid tumors. Here, we investigate the potential of miR-155, a microRNA known to play an important role in CD8 + T cell fitness. We show that forced expression of miR-155 in tumor antigen-specific T cells improves the tumor control of B16 tumors expressing a low-affinity antigen ligand. Importantly, miR-155-transduced T cells exhibit increased proliferation and effector functions associated with a higher glycolytic activity independent of exogenous glucose. Altogether, these data suggest that miR-155 may optimize the antitumor activity of adoptively transferred low-affinity tumor-infiltrating lymphocytes (TILs), in particular, by rendering them more resistant to the glucose-deprived environment of solid tumors. Thus, transgenic expression of miR-155 may enable therapeutic targeting of self-antigen-specific T cells in addition to neoantigen-specific ones.

Breast cancer cell–derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function

“…miR-155 in the tumors is derived from both cancer cells and stroma cells including immune cells. While we and others showed the anti-tumor role of immune cell miR-155 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the role of cancer cell-derived miR-155 is more elusive or controversial (5,8). To investigate the direct impact of cancer cell-derived miR-155 on tumor progression and tumor immune infiltration, we established B-cell integration cluster (Bic, miR-155 gene) overexpressing breast cancer cell lines (EO771-Bic, 4T1-Bic, and AT-3-Bic) via lentiviral transduction; these cells express 15-60-fold higher miR-155 than control lentiviral transduced cells (EO771-GFP, 4T1-GFP, and AT-3-GFP) (Supplemental Figure 5, A-C).…”

“…Nevertheless, some reports have shown that miR-155 upregulation in tumors is associated with improved overall survival of patients with several types of cancer including breast cancer, colon cancer, and melanoma (7)(8)(9). To account for this discrepancy, we and others have shown that miR-155 may play a central role in innate and adaptive immune responses (10)(11)(12)(13)(14)(15)(16). We reported that miR-155 deficiency in macrophages and myeloid-derived suppressor cells (MDSCs) promotes tumor growth by exaggerating the immunosuppressive functions of these cells (12,13).…”

MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment

“…Cytotoxic T cells are considered one of the most powerful anti-tumoral ICs, but they are often absent or dysfunctional, due to their exhaustion or to the immunosuppressive features of the TME [ 11 ]. They exert anti-tumoral activity by directly killing malignant cells through the release of granules of perforin and granzyme B. Clinically, high levels of T cells correlate with good prognosis in several cancers—such as melanoma, breast, lung, ovarian, renal, prostate, and gastric [ 99 ]—and in recent years, immunotherapy approaches have been developed to foster the anti-tumoral capacity of T cells [ 85 ].…”

microRNAs Shape Myeloid Cell-Mediated Resistance to Cancer Immunotherapy

“…Yan and coworkers demonstrated that miR-155-induced downregulation of TIM3, a negative immune checkpoint, enhanced the cytolytic activity of anti-HCC CD8 + T cells (56). Finally, miR-155 overexpression can optimize CD8 + T cell antitumor activity and improve adoptive-transfer in low-affinity antigen tumors (57).…”