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STING-induced regulatory B cells compromise NK function in cancer immunity.

ABSTRACT: An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers^1-3. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression⁴. Although these agonists hold promise as potential cancer therapies⁵, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear^5-7. Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35⁺ regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING-IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.

SUBMITTER: Li S

PROVIDER: S-EPMC9875944 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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STING-induced regulatory B cells compromise NK function in cancer immunity.

Li Sirui S Mirlekar Bhalchandra B Johnson Brandon M BM Brickey W June WJ Wrobel John A JA Yang Na N Song Dingka D Entwistle Sarah S Tan Xianming X Deng Meng M Cui Ya Y Li Wei W Vincent Benjamin G BG Gale Michael M Pylayeva-Gupta Yuliya Y Ting Jenny P-Y JP

Nature 20221005 7931

An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers1-3. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression4. Although these agonists hold promise as potential cancer therapies5, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear5-7. ...[more]

PMID: 36198789

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Project description:BackgroundGiven the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis.Principal findingsHere we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naïve mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-γ, TNF-α, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL.ConclusionsOur data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas.

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STING-induced regulatory B cells compromise NK function in cancer immunity.

Publications

STING-induced regulatory B cells compromise NK function in cancer immunity.

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