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Simple Summary: Antibody–drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs) are two promising therapeutic modalities against many types of cancers. However, many patients develop resistance. The resistance mechanisms to ADCs and ICIs have been comprehensively illuminated in this review. A combination of ADCs and ICIs has been explored to overcome resistance to ADC or ICI single treatment. Recently, a clinical study demonstrated that a combination of enfortumab vedotin (EV), an ADC against Nectin-4, with the ICI pembrolizumab achieves remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma. The underlying mechanism is likely due to the enhancement of pembrolizumab-induced anticancer immunity mediated by EV. With the emerging use of combination therapy strategy, it is critical to understand the mechanism of successful and/or failed clinical studies for the future development of combination therapy of ADCs with ICIs. Antibody–drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells and a small molecule chemotherapy payload that is conjugated to the antibody via a linker. ADCs are one of the most promising therapeutic modalities for the treatment of various cancers. However, many patients have developed resistance to this form of therapy. Extensive efforts have been dedicated to identifying an effective combination of ADCs with other types of anticancer therapies to potentially overcome this resistance. A recent clinical study demonstrated that a combination of the ADC enfortumab vedotin (EV) with the immune checkpoint inhibitor (ICI) pembrolizumab can achieve remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC)—leading to the first approval of a combination therapy of an ADC with an ICI for the treatment of cancer patients. In this review, we highlight knowledge and understanding gained from the successful development of EV and the combination therapy of EV with ICI for the treatment of la/mUC. Using urothelial carcinoma as an example, we will focus on dissecting the underlying mechanisms necessary for the development of this type of combination therapy for a variety of cancers. [ABSTRACT FROM AUTHOR]

T helper 1 ([T.sub.H]1) differentiation and IFN-[gamma] production are crucial in cell-mediated immune responses. IL-12 is an important regulator of this process and mediates its effects through signal transducer and activator of transcription 4 (STAT4). IFN-[gamma] production is also regulated by the p38 mitogen-activated kinase pathway, although the mechanisms are ill-defined. We show here that GADD45-[beta] and GADD45-[gamma] can induce STAT4 S721 phosphorylation via the MKK6/ p38 pathway. Thus, STAT4 could be a target that accounts for the defects in cell-mediated immunity associated with perturbations in the p38 pathway. To investigate the biological significance of STAT4 S721 phosphorylation, we reconstituted primary spleen cells from STAT4-deficient mice with wild-type and mutated STAT4, by using a retroviral gene transduction. We demonstrated that expression of wild-type STAT4, but not the S721A mutant, restored normal [T.sub.H]1 differentiation and IFN-[gamma] synthesis. The inability of STAT4 S721 to restore IFN-[gamma] production was not caused by decreased IL-12R expression because the STAT4 S721 mutant also failed to restore IFN-[gamma] production in STAT4-deficient IL-12R[beta]2 transgenic cells. Importantly, STAT4 S721A-transduced cells showed normal proliferative response to IL-12, illustrating that serine phosphorylation is not required for IL-12-induced proliferation. Additionally, the results imply the existence of STAT4 serine phosphorylation-dependent and -independent target genes. We conclude that phosphorylation of STAT4 on both tyrosine and serine residues is important in promoting normal [T.sub.H]1 differentiation and IFN-[gamma] secretion.

Interleukin-13 (IL-3) is a cytokine secreted by Th2 lymphocytes that is capable of inducing expression of 15-lipoxygenase (15-LO) in primary human monocytes. We recently demonstrated that induction of 15-LO requires the activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6. Since IL-13-induced 15-LO expression was inhibited by H7 (a serine-threonine kinase inhibitor), we predicted that Stat serine phosphorylation may also be crucial for 15-LO expression. In this study, we present evidence indicating that IL-13-induced 15-LO mRNA expression was detectable as early as 1 h by real-time reverse transcription-PCR. We found that IL-13 induced a time-dependent serine phosphorylation of both Stat1 and Stat3, detectable at 15 min after IL-13 treatment. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) was detected in a time-dependent fashion, with peak phosphorylation at 15 min after IL-13 treatment. SB202190, a p38 MAPKspecific inhibitor, markedly inhibited IL-13-induced Stat1 and Stat3 serine phosphorylation as well as DNA binding. Furthermore, treatment of cells with Stat1 or Stat3 decoys significantly impaired IL-13-induced 15-LO expression. Taken together, our results provide the first evidence that IL-13 induces p38 MAPK phosphorylation/activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. Both of these events are important steps in IL-13-induced 15-LO expression in human monocytes. [ABSTRACT FROM AUTHOR]