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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are the most abundant immune cells, which act as a key regulator in tumorigenesis and progression. Increasing evidence have demonstrated that the TME alters the nature of macrophages to maintain dynamic tissue homeostasis, allowing TAMs to acquire the ability to stimulate angiogenesis, promote tumor metastasis and recurrence, and suppress anti-tumor immune responses. Furthermore, tumors with high TAM infiltration have poor prognoses and are resistant to treatment. In the field of solid tumor, the exploration of tumor-promoting mechanisms of TAMs has attracted much attention and targeting TAMs has emerged as a promising immunotherapeutic strategy. Currently, the most common therapeutic options for targeting TAMs are as follows: the deletion of TAMs, the inhibition of TAMs recruitment, the release of phagocytosis by TAMs, and the reprogramming of macrophages to remodel their anti-tumor capacity. Promisingly, the study of chimeric antigen receptor macrophages (CAR-Ms) may provide even greater benefit for patients with solid tumors. In this review, we discuss how TAMs promote the progression of solid tumors as well as summarize emerging immunotherapeutic strategies that targeting macrophages.

During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.

Abstract The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an \"off-the-shelf\" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

Background The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients. Methods We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para‐tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured. Results Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα + or PD1 + TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non‐HBV‐infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis. Conclusion Hyperactivated CD47/SIRPα and PD1/PD‐L1 signals in CD68 + TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.

Long noncoding RNAs (lncRNAs) play crucial roles in regulating a variety of biological processes in lung adenocarcinoma (LUAD). In our study, we mainly explored the functional roles of a novel lncRNA long intergenic non-protein coding RNA 1426 (LINC01426) in LUAD. We applied bioinformatics analysis to find the expression of LINC01426 was upregulated in LUAD tissue. Functionally, silencing of LINC01426 obviously suppressed the proliferation, migration, epithelial–mesenchymal transition (EMT), and stemness of LUAD cells. Then, we observed that LINC01426 functioned through the hedgehog pathway in LUAD. The effect of LINC01426 knockdown could be fully reversed by adding hedgehog pathway activator SAG. In addition, we proved that LINC01426 could not affect SHH transcription and its mRNA level. Pull-down sliver staining and RIP assay revealed that LINC01426 could interact with USP22. Ubiquitination assays manifested that LINC01426 and USP22 modulated SHH ubiquitination levels. Rescue assays verified that SHH overexpression rescued the cell growth, migration, and stemness suppressed by LINC01426 silencing. In conclusion, LINC01426 promotes LUAD progression by recruiting USP22 to stabilize SHH protein and thus activate the hedgehog pathway.

Background BCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells. Methods This study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis. Results We compared the heterogeneity of CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT + NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1β hi Mφ, S100A9 hi Mφ, interferon-responsive Mφ, CD16 hi Mφ, MARCO hi Mφ, and S100A11 hi Mφ significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell–cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy. Conclusion Taken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings.

Abstract Background: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. Methods: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45+ BM cells were enriched with human CD45 microbeads. The CD45+ cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. Results: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. Conclusions: This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.

Nonsyndromic orofacial clefts (NSOFCs) are the most common human craniofacial defects. Genetic factors play a critical role in the pathogenesis of NSOFCs. However, known causal genes only explain a minority of the estimated heritability. To unveil the underlying genetic architecture, exome sequencing is performed on 214 sporadic patients with NSOFCs. The findings substantiate the genetic and allelic heterogeneity of NSOFCs and underscore the crucial role of dysregulation of OFC‐related signaling pathways in the occurrence of NSOFCs. Besides, the candidate variants discovered provide a fruitful resource for further genetic studies. Particularly, three BOC missense variants (p.R407W, p.G436S, and p.D1018N) are identified in three unrelated cases with cleft palate. In parallel, a BOC nonsense variant (p.R681X), co‐segregating with a GLI2 missense variant (p.A543G), is identified in a multiplex family with microform cleft lip. Functional studies demonstrate while the four BOC variants are hypomorphic alleles, the GLI2 variant is a hypermorphic allele. The counteraction between BOC p.R681X allele and GLI2 p.A543G allele accounts for the mild phenotype in the multiplex family. Thus, this study establishes BOC as a novel causal gene and implicates a two‐locus model of inheritance via the epistatic antagonism of two SHH pathway variants in NSOFCs. Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial defects. Exome sequencing of 214 sporadic cases sheds new light on its genetic architecture and identifies many candidate pathogenic variants. Furthermore, functional studies establish BOC as a novel causal gene and reveal an unusual two‐locus model of inheritance via the epistatic antagonism of two SHH pathway variants in NSOFCs.