Abstract Immunotherapy has achieved significant success in treating various cancers, yet its efficacy in castration resistant prostate cancer (CRPC) is minimal, partly due to the lack of intratumoral immune effector cells in CRPC. Understanding the mechanisms of immune evasion and identifying potential therapeutic strategies to activate innate antitumor immunity are crucial for enhancing the response to immunotherapy. Here we demonstrate that PKMYT1, a member of the WEE1 family, is overexpressed in CRPC tissues. Patients with high PKMYT1 expression exhibit low CD8+ T cells infiltration and resistance to immune checkpoint blockade (ICB). Targeting PKMYT1 can suppress CRPC progression, accompanied with increased intratumoral CD8+ T cells. Selective PKMYT1 inhibitor, RP-6306, augments ICB at the presence of CD8+ T cells. PKMYT1 inhibitor alone or in combination with PD-L1 blockade increases infiltration of CD8+ T cell and remarkable tumor suppression in vivo. Mechanically, targeting PKMYT1 activates the cGAS-STING pathway, enhances interferon signaling, and elevates key immune modulators, including CCL5 and CXCL10. These findings highlight a key role of PKMYT1 in CRPC progression and suggest PKMYT1 as a potential therapeutic target in combination with ICB.

The spleen is critical for immunity. It is the largest immune organ and immune center in the peripheral system. While the relationship between behavior and immunity has been demonstrated in physiology and diseases, the role of the spleen in behavior is not clear. To investigate the effects of the spleen on behaviors, we performed a refined splenectomy procedure on C57BL/6J mice and performed an open field test, circadian rhythm test, elevated plus maze, sucrose preference test, and Barnes maze test. Splenectomy did not induce changes in general locomotion, circadian rhythms, learning and memory, or depression/anxiety-related behaviors. To further investigate the effects of spleen on stress susceptibility, we established mouse models of depression through chronic unpredictable mild stress. The behavioral performances of mice subjected to splenectomy showed no differences from control animals. These findings suggest that splenectomy does not cause changes in baseline behavioral performance in mice.

The threat of new viral outbreaks has heightened the need for ready-to-use vaccines that are safe and effective. Here we show that a subcutaneous vaccine consisting of live Zika virus electrostatically entrapped in a self-adjuvanting hydrogel recruited immune cells at the injection site and provided mice with effective protection against a lethal viral challenge. The hydrogel prevented the escape of the viral particles and upregulated pattern recognition receptors that activated innate antiviral immunity. The local inflammatory niche facilitated the engulfment of the virus by immune cells infiltrating the hydrogel, the processing and cross-presentation of antigens and the expansion of germinal centre B cells and induced robust antigen-specific adaptive responses and immune memory. Inflammatory immune niches entrapping live viruses may facilitate the rapid development of safe and efficacious vaccines.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

B-cell acute lymphoblastic leukemia (B-ALL) reflects the malignant counterpart of developing B cells in the bone marrow (BM). Despite tremendous progress in B-ALL treatment, the overall survival of adults at diagnosis and patients at all ages after relapse remains poor. Galectin-1 (GAL1) expressed by BM supportive niches delivers proliferation signals to normal pre-B cells through interaction with the pre-B cell receptor (pre-BCR). Here, we asked whether GAL1 gives non-cell autonomous signals to pre-BCR+ pre-B ALL, in addition to cell-autonomous signals linked to genetic alterations. In syngeneic and patient-derived xenograft (PDX) murine models, murine and human pre-B ALL development is influenced by GAL1 produced by BM niches through pre-BCR-dependent signals, similarly to normal pre-B cells. Furthermore, targeting pre-BCR signaling together with cell-autonomous oncogenic pathways in pre-B ALL PDX improved treatment response. Our results show that non-cell autonomous signals transmitted by BM niches represent promising targets to improve B-ALL patient survival.
© 2023 The Author(s).

cGAS/DncV-like nucleotidyltransferase (CD-NTase) family members are immune sensors that synthesize diverse nucleotide signals to initiate antiviral response in bacteria and animals. As a founding member of CD-NTase enzyme, cGAS has been identified as a key sensor for cytoplasmic DNA and type I interferons (IFNs) signaling in metazoan. However, the functions of other metazoan CD-NTases remain enigmatic. Here, we showed that Mab-21 domain-containing protein 2 (MB21D2), another member of the CD-NTase family, plays a positive role in modulating the cGAS-STING signaling in myeloid cells. Deficiency of MB21D2 in THP-1 cells or mice macrophages led to impaired production of type I interferon upon DNA stimulation. Consistently, Mb21d2-/- mice showed more susceptible to infection with DNA virus and faster growth of melanoma, compared to its counterparts. Mechanistically, MB21D2 specially bound with the N-terminal of cGAS, facilitated its liquid phase condensation and DNA-binding activity, leading to the enhanced production of cGAMP and subsequent IFN-β production. Thus, our findings unveiled that the CD-NTase family member MB21D2 contributes to host antiviral and antitumor responses by enhancing cGAS activation.
© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.