Cancer immunology research最新文献

Immunotherapies have had unprecedented success in the treatment of multiple cancer types, albeit with variable response rates. Unraveling the complex network of immune cells within the tumor microenvironment (TME) may provide additional insights to enhance antitumor immunity and improve clinical response. Many studies have shown that NK cells or innate lymphoid cells (ILC) have regulatory capacity. Here, we identified CD103 as a marker that was found on CD56+ cells that were associated with a poor proliferative capacity of tumor-infiltrating lymphocytes in culture. We further demonstrated that CD103+CD56+ ILCs isolated directly from tumors represented a distinct ILC population that expressed unique surface markers (such as CD49a and CD101), transcription factor networks, and transcriptomic profiles compared with CD103-CD56+ NK cells. Using single-cell multiomic and spatial approaches, we found that these CD103+CD56+ ILCs were associated with CD8+ T cells with reduced expression of granzyme B. Thus, this study identifies a population of CD103+CD56+ ILCs with potentially inhibitory functions that are associated with a TME that includes CD8+ T cells with poor antitumor activity. Further studies focusing on these cells may provide additional insights into the biology of an inhibitory TME.

Biomarkers of responsiveness to immune checkpoint blockade (ICB) are heavily sought given the breadth and depth of the use of ICB in cancer. PD-L1 expression was among the first biomarkers identified, but multiple factors have precluded more widespread use. In this issue, Galsky and colleagues utilize two separate PD-L1 assays to study urothelial carcinoma specimens and observe that SP142 (relative to 22C3) preferentially stains dendritic cells. These observations may help reconcile the discordant performance of the two PD-L1 assays in ICB-treated urothelial carcinoma while underscoring the role of dendritic cells in orchestrating ICB response. See related article by Galsky et al., p. XX .

Agonistic anti-CD40 with anti-PD-1 can elicit objective responses in a small number of patients with pancreatic ductal adenocarcinoma (PDA). Better understanding of their individual effects on the PDA tumor microenvironment will help inform new strategies to further improve outcomes. Herein, we map tumor-specific CD8+ T-cell differentiation following agonistic anti-CD40 and/or anti-PDL1 in PDA. Rare Tcf1+Slamf6+ CD8+ T cells (TSTEM) are shown to seed memory precursors that transition into a continuum of exhausted and effector T cells. In tumors, anti-PDL1 drove the clonal expansion of Gzmk+ progenitor exhausted (CD8+ T cells, whereas anti-CD40 promoted CD4+ T-cell clonal expansion and accumulation of CD8+ TTSTEM. Cloning the most frequent intratumoral T-cell receptors (TCRs) revealed identical neoepitope specificity, yet the top TCRs from anti-PDL1  anti-CD40 cohorts lacked tetramer binding suggesting lower affinity. Anti-CD40 + anti-PDL1 markedly drove the clonal hyperexpansion of a unique exhausted T-cell (TEX) subset in spleen. TEX were enriched for IL2R, and provision of IL-15 complex (IL-15C) mitigated systemic and intratumoral T-cell exhaustion when combined with anti-CD40 + anti-PDL1, resulting in enhanced antitumor effects, prolongation of animal survival, and resistance to orthotopic tumor rechallenge. Mechanistically, while anti-CD40 + anti-PDL1 mitigated Tox, IL-15C + anti-CD40 + anti-PDL1 increased T-bet thereby conferring a higher T-bet:Tox ratio in tumor-specific CD8+ T cells. Collectively, agonistic anti-CD40 and anti-PDL1 drove systemic and intratumoral CD8+ T-cell clonal expansion and acquisition of exhaustion features. Provision of IL-15C altered the trajectory of T-cell differentiation induced by immunotherapy, resulting in PDA eradication and long-lived antitumor memory T cells.

mRNA vaccines are recognized as potent tools for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. Here, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNPs) to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained STING-mediated interferon (IFN) response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment and antigen presentation by antigen-presenting cells (APCs) both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination has shown a robust adjuvant effect, amplifying the potency of mRNA and protein vaccines by inducing strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted synergistic antitumor effects with IFNγ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS-mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.

Immune checkpoint blockade (ICB) has revolutionized the therapeutic landscape across various cancer types. However, the emergence of resistance to ICB therapy limits its clinical application. Therefore, it is necessary to better understand immune-resistance mechanisms that could be targeted by actionable drugs, and important to identify predictive markers for selecting patients. Here, by analyzing transcriptomic data from patients treated with PD-1 blockade and tumor models refractory to anti-PD-1 therapy, we identified WEE1 as a resistance factor conferring cancer stem cell (CSC)-like properties as well as immune-refractory phenotypes to tumor cells. WEE1 is transcriptionally upregulated by stemness factor NANOG and predominantly localized in the cytoplasm, not the nucleus, following AKT-dependent S642 phosphorylation in immune-refractory tumor cells. Mechanistically, cytoplasmic WEE1 drove AKT hyperactivation via the HSP90A/TCL1A/AKT auto-amplification loop andupregulated the expression of refractory factors such as CYCLIN A for hyperproliferation and MCL-1 for resistance to T cell killing. Of note, CXCL10 was downregulated, resulting in insufficient T cell infiltration. The NANOG/WEE1/AKT axis was also conserved in various human cancers. Importantly, targeting WEE1 with a clinically relevant inhibitor sensitized NANOG+ immune-refractory tumors to ICB, reinvigorating antitumor immunity by disrupting the HSP90A/TCL1A/AKT loop. Thus, our findings demonstrate the oncogenic role of cytoplasmic WEE1 in immune-refractoriness and CSC-like properties of tumor cells through AKT hyperactivation and provide a rationale for combining a WEE1 inhibitor to control anti-PD-1 therapy-refractory tumors.

Cytotoxic chemotherapy that kills cancer cells can also elicit anti-tumor immune responses. Therefore, understanding the immunogenic context of cytotoxic chemotherapy can improve combination immunotherapies. In this study, we sought to improve our understanding about dendritic cell (DC) dynamics in cytotoxic chemotherapy-treated tumor tissues by developing 3D microfluidic devices that enable high-resolution visualization of cellular dynamics. Specifically, microfluidic chips mimicking 3D tumor tissues were fabricated and used. Collagen gel blocks encapsulating cancer cells in microfluidics were treated with various concentrations of oxaliplatin (OXP). Then, DCs were attached on the side of the collagen gel blocks, and migration of DCs within the 3D gels was quantitatively analyzed. Interactions between OXP-treated cancer cells and DCs were observed by high-resolution time-lapse imaging. Active infiltration of DCs was predominantly observed when OXP was administrated, indicating OXP-treated cancer cells release factors promoting DC motility. The highest frequency of DC recruitment was detected at a moderate OXP concentration, suggesting that optimizing the dosage of cytotoxic chemotherapy is crucial in order to improve immunogenic cell death (ICD). High-resolution video microscopy revealed that DCs employ trogocytosis to disassemble dying/dead cancer cells and acquire antigens, as opposed to phagocytosing the entire cancer cells. Microfluidic chip-based observations may provide new insights for the design of new therapeutic strategies to combine chemotherapy and immunotherapy.

The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated the Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.

CD8+ T-cell abundance is insufficient to assess antitumor immunity and shows poor performance in predicting breast cancer prognosis and immunotherapy response, presumably owing to the complexity of CD8+ T-cell functionalities. Although single-cell RNA sequencing can dissect the multifaceted functions of CD8+ T cells for better immune assessment, its clinical application is limited. In this study, we developed bulk RNA sequencing-based FuncDimen models from integrative analysis of single-cell RNA sequencing and matched bulk RNA sequencing data to evaluate CD8+ T-cell functionalities across five dimensions: tumor reactivity, cytotoxicity, IFNγ secretion, proliferation, and apoptosis. The FuncDimen models quantifying different functional dimensions of CD8+ T cells were validated in our breast cancer cohort and external databases using immunofluorescence and imaging mass cytometry. We calculated the FuncAggre score by weighted aggregation of all five FuncDimen models to encapsulate the overall antitumor immunity. In our breast cancer cohort and external databases, the FuncAggre score demonstrated superior predictive performance for breast cancer prognosis (time-dependent AUC: 0.56-0.70) and immunotherapy response (AUC: 0.71-0.83) over other immune biomarkers, regardless of the breast cancer molecular subtype. Together, the FuncDimen models offer a refined assessment of antitumor immunity mediated by CD8+ T cells in the clinic, enhancing prognostic prediction and aiding personalized immunotherapy in breast cancer.

The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment and promotes tumor progression remain unclear. In this study, we investigated the expression and function of complement C5a receptor 1 (C5aR1) in human and mouse cancer-associated dendritic cells (DC). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared with DCs from the blood or spleen. C5aR1 expression was restricted to type 2 conventional DCs and monocyte-derived DCs, which displayed a tolerogenic phenotype capable of inhibiting T-cell activation and promoting tumor growth. C5aR1 engagement in DCs drove their migration from tumors to tumor-draining lymph nodes, where C5a levels were higher. We used this knowledge to optimize an anticancer therapy aimed at enhancing DC activity. In three syngeneic tumor models, C5aR1 inhibition significantly enhanced the efficacy of poly I:C, a Toll-like receptor 3 agonist, in combination with PD-1/PD-L1 blockade. The contribution of C5aR1 inhibition to the antitumor activity of the combination treatment relied on type 1 conventional DCs and antigen-specific CD8+ T cells, required lymphocyte egress from secondary lymphoid organs, and was associated with an increase in IFNγ signaling. In conclusion, our study highlights the importance of the C5a/C5aR1 axis in the biology of cancer-associated DCs and provides compelling evidence for the therapeutic potential of modulating the complement system to enhance DC-mediated immune responses against tumors.

Radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) therapy has attracted substantial attention due to its potential to improve outcomes for patients with several types of cancer. However, the optimal administration timepoints and drug combinations remain unclear because the mechanisms underlying RT-induced changes in immune checkpoint molecule expression and interaction with their ligand(s) remain unclear. In this study, we demonstrated the dynamics of lymphocyte-mediated molecular interactions in tissue samples from patients with esophageal cancer throughout RT schedules. Single-cell RNA sequencing and spatial transcriptomic analyses were performed to investigate the dynamics of these interactions. The biological signal in lymphocytes transitioned from innate to adaptive immune reaction, with increases in ligand-receptor interactions, such as PD-1-PD-L1, CTLA4-CD80/86, and TIGIT-PVR interactions. A mathematical model was constructed to predict the efficacy of five types of ICIs when administered at four different timepoints. The model suggested that concurrent anti-PD-1/PD-L1 therapy or concurrent/adjuvant anti-CTLA4/TIGIT therapy would exert a maximal effect with RT. This study provides rationale for clinical trials of RT combined with defined ICI therapy, and these findings will support future studies to search for more effective targets and timing of therapy administration.