SUMMARY The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4–1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.
The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8 þ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8 þ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras-and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8 þ T cells. Distinct from its action on CD4 þ T cells, IL35 signaling in gp130 þ CD8 þ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8 þ T cells via suppression of CXCR3, CCR5, and IFNg expression. Inhibition of STAT3 signaling in tumor-educated CD8 þ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8 þ T cells was driven by B cell-but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8 þ T-cell activation independently of effector or regulatory CD4 þ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35 þ B-cell subset in patients with PDA and demonstrated that the presence of IL35 þ cells predicted increased occurrence of phosphorylated (p)Stat3 þ CXCR3 À CD8 þ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/ STAT3 signaling as an important direct link to CD8 þ T-cell exclusion and immunotherapy resistance in PDA.
Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4 effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8 T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically "cold" to "hot" tumor. Although PDA is typically resistant to anti-PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti-PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy. .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.