B cells imprint adoptively transferred CD8⁺T cells with enhanced tumor immunity

Abstract

BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell—B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B–T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

Intratumoral immunotherapy relies on B and T cell collaboration

“…Here, we demonstrated this in the context of immunotherapy, showing that B cells activated T cells in vitro and in situ at the tumor in an MHC-dependent and tumor antigen–specific manner. These activated T cells did not acquire a signature of low CD39, high ICOS, and IL-2 receptor α, as was observed in a T cell transfer study where CpG-activated B cells were used for T cell expansion ( 41 ), perhaps due to differences in our experimental procedure. We did not specifically evaluate T cell activation by other immune cells in the LN, but T cell activation in the absence of B cells was minimal.…”

“…These activated T cells also had increased expression of other activation markers, including CD86 and CD134, but not negative immunoregulatory receptors and activation markers such as PD1, GITR, CD39, ICOS, CD25, or CD80 (fig. S12, B and C), which are also associated with recent antigen encounter and prolonged persistence in vivo ( 41 ).…”

Immune profiling identifies CD8+ T-cell subset signatures as prognostic markers for recurrence in papillary thyroid cancer

“…In lung cancer with a more advanced stage, the fractions of PD-1 + CD39 + CD8 + T cells tend to be higher ( 51 ). PTC patients with PD-1 - CD39 + CD103 + CD8 + T cells had decreased B cells and mDC ( Figure 6A ), which are essential for CD8 + T-cell activation and antitumor response ( 52 , 53 ). In addition, our research showed that CD8 + T cells in these patients were also in a state of impaired function with low expressions of cytotoxic molecules and perforin, which is critical for antitumor immunity ( 46 ) ( Figure 6B ).…”

Regulation of CD8 T cell by B-cells: A narrative review

“…In addition, one study demonstrated that ex vivo expansion of CD8 T cells for adoptive T cell transfer was achieved using TLR-activated B cells. CD8 T cells acquired a unique IL-2Rα high ICOS high CD39 low phenotype and an altered metabolic profile, all dependent on the B cells present in the culture ( 52 ). Further evidence that B cells play a positive role in cancer control is derived from mouse models.…”

“…However, these B cells lack the capacity to induce CD8 memory T cells compared to dendritic cell (DC) immunization with a decreased expression of the transcription factors Bcl-6 in CD8 effector cells after CD40-B cell immunization compared to DC ( 67 ). In a mouse model of anti-tumor immunity, the TLR9 agonist CpG has been shown to enhance the CD8 T cell response in vitro , in a B cell and contact-dependent manner, resulting in an improved tumor growth control and a higher mouse survival ( 52 ). Tumor-specific murine CD8 T cells [derived from splenocytes of plem-1 T cell receptor (TCR) transgenic mice] were conditioned in vitro using TLR9 - activated B – cells.…”