Cancer Immunology, Immunotherapy最新文献

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

Neutrophils are integral to the frontline defense against pathogenic bacterial and fungal invasions. Beyond their traditional roles, these cells are increasingly recognized for their dualistic contributions to the pathology of autoimmune and inflammatory diseases, as well as their complex involvement in cancer progression. Neutrophils interact with different disease states, highlighting their potential as therapeutic targets. Within tumor microenvironment (TME), tumor-associated neutrophils (TANs) exhibit a functional dichotomy, capable of either fostering or impeding tumor growth and metastasis. This binary functional potential of TANs, under certain conditions, suggests a reversible state that could transition from tumor-promoting to tumor-eradicating phenotypes. Despite the critical implications of such functional plasticity, systematic studies of TAN behavioral shifts in the context of cancer immunotherapy remain scarce. Herein, we review recent advancements in the understanding of TANs within the TME, highlighting their binary regulatory effects on solid tumors. Leveraging the latest insights from experimental and clinical research, this review elucidates the complex roles of TANs in tumor development and explores their molecular interactions as potential therapeutic targets. The elucidation of these mechanisms holds promise for novel cancer treatment strategies, aiming to improve patient outcomes by manipulating the tumor-promoting or -suppressing functions of TANs.

Background: Combination immunotherapy is the current standard for treating advanced hepatocellular carcinoma (HCC). The response elicited by upfront immune checkpoint inhibitors (ICIs) might influence the efficacy of salvage therapy, a phenomenon known as the carry-over effect. This effect is thought to stem from immune memory and sustained immune activation, providing extended protection against tumor progression and resulting in a durable response even after discontinuation of ICI. This study aimed to investigate the carry-over effect of first-line ICI therapy in patients with advanced HCC.

Methods: Patients who received first-line ICI therapy for advanced HCC from December 2017 to December 2021 were included if they exhibited disease progression and received second-line systemic therapy. We analyzed the associations between clinical benefit (classified as complete, partial response and stable disease) of first-line ICI therapy, post-progression survival (PPS) and second-line progression-free survival (PFS). We used a historical cohort of patients receiving first-line multikinase inhibitor (MKI) for comparison.

Results: A total of 137 patients were analyzed. We included 60 patients who received first-line ICI therapy, of which clinical benefit was detected in 46 (76.7%). Compared with patients without clinical benefit of first-line ICI therapy, patients with clinical benefit exhibited significantly longer PPS (median: 14.6 vs. 4.9 months, P = 0.024) and second-line PFS (median: 3.6 vs. 1.6 months, P = 0.027). In multivariate analysis, clinical benefit of first-line ICI therapy remained an independent predictor of PPS [hazard ratio (HR): 0.295, P = 0.005] and second-line PFS (HR: 0.484, P = 0.047). Conversely, clinical benefit was not associated with PPS among patients receiving first-line MKI therapy in both univariate and multivariate analysis in historical MKI cohort.

Conclusions: Clinical benefit of first-line ICI therapy was associated with PPS and second-line PFS in patients with advanced HCC, suggestive of the carry-over effect of ICI.

It is common knowledge that mast cells (MCs) exert different roles in the gastrointestinal tract, from the maintenance of homeostasis to the onset and propagation of different gut diseases such as food allergies, infections, inflammation, and cancer. However, the mechanisms through which MCs dialog and influence the intestinal tissue are not completely known. To get insight into the bidirectional crosstalk between MCs and the intestinal microenvironment, both in homeostatic and pathological settings, colon organoids from intestinal epithelium of healthy mice and adenomas from AOM/DSS-treated mice have been exploited and co-cultured with MCs. The influence of MCs on organoid architecture and the effect of healthy and tumoral organoids on the phenotype and responsiveness of MCs have been addressed. We observed that MCs interact with intestinal organoids and contribute to the differentiation of healthy organoids by upregulating the expression of mucin-2, chromogranin A, cadherin-1, and claudin 4. On the contrary, in co-culture with tumoral organoids a decrease in cell proliferation, chromogranin A, and lysozyme expression was observed. Tumoral organoids have been shown to activate MCs via the IL-33/ST2 axis leading to increased release of TNF-α which in turn was responsible for the observed effects on tumoral organoids. Our results indicate that MCs are important mediators of intestinal tissue homeostasis and that a different environment can shape and direct MCs toward the dampening or propagation of the inflammatory response. Ultimately, our MC-organoid co-cultures represent a valid in vitro tool to investigate the role of MCs in the gut.

Background: Glioma, a prevalent malignant intracranial tumor, exhibits limited therapeutic efficacy due to its immunosuppressive microenvironment, leading to a poor prognosis for patients. ARHGDIB is implicated in the remodeling of the tumor microenvironment and plays a significant role in the pathogenesis of various tumors. However, its regulatory effect within the immune microenvironment of glioma remains unclear.

Methods: The mRNA expression pattern of ARHGDIB was analyzed using public databases, and its expression was further validated in our collected cohort through quantitative PCR (qPCR) and immunohistochemistry (IHC). Kaplan-Meier survival analysis and LASSO-Cox regression were employed to ascertain the clinical significance of ARHGDIB in glioma. Subsequently, we systematically evaluated the association between ARHGDIB expression and immune characteristics within the glioma microenvironment, as well as its potential to predict treatment response in glioma. Additionally, in vitro experiments were conducted to elucidate the role of ARHGDIB in remodeling the glioma microenvironment and promoting tumor malignancy progression.

Results: Combined with bioinformatics analysis of public databases and validation with qPCR and IHC on our cohort, our findings indicate that ARHGDIB is markedly overexpressed in glioma and correlates with poor patient prognosis, thereby serving as a potential biomarker for adverse outcomes in glioma. Functional enrichment and immune infiltration analyses reveal that ARHGDIB is implicated in the recruitment of immunosuppressive cells, such as M2 macrophages and neutrophils, contributing to the alteration of the glioma immunosuppressive microenvironment and hindering the immune response. Further investigations through single-cell sequencing, immunohistochemistry, immunofluorescence, and in vitro experiments demonstrate that ARHGDIB exhibits an expression pattern akin to CD163, with its overexpression inducing M2 macrophage polarization and facilitating glioma cell proliferation and migration.

Conclusions: ARHGDIB emerges as a novel marker for tumor-associated macrophages, playing a crucial role in shaping the immunosuppressive microenvironment and representing a promising prognostic biomarker for glioma.

Background: Natural killer (NK) cells are a subset of innate lymphoid cells that possess cytotoxic properties, playing a pivotal role in immune surveillance against tumor cells. However, it remains unclear whether there are any alterations in the quantity and functional status of NK cells in colorectal cancer (CRC).

Methods: In this study, we collected peripheral blood samples from both CRC patients and age- and sex-matched healthy controls (HCs). The distribution characteristics, phenotypic changes, functional status, apoptosis susceptibility, and proliferative capacity of circulating NK cells were detected and analyzed by flow cytometry. An in vitro study was performed to investigate the blocking effect of KLRG1 antibody on peripheral blood NK cells in CRC patients.

Results: The frequency and absolute number of circulating NK cells were significantly decreased in CRC patients compared to those in HCs. Meanwhile, the function of NK cells from CRC patients was compromised, as shown by the reduced production of IFN-γ, TNF-α, and CD107a, with this impairment becoming increasingly significant as neural invasion progressed and tumor invasion advanced. We further found that the expression of activating receptors NKp30 and NKp46 were reduced, while the expression of inhibitory receptor KLRG1 was remarkably increased. The increased proportion of KLRG1 on NK cells was associated with CRC progression, and KLRG1⁺ NK cells showed impaired production of IFN-γ, TNF-α, and CD107a and were more susceptible to apoptosis. Importantly, blockade of the KLRG1 pathway could restore the cytokine production and degranulation ability of NK cells from CRC patients.

Conclusions: The present study demonstrates that NK cells in CRC patients exhibit functional exhaustion, and KLRG1 blockade restores the effector function of NK cells, indicating that targeting KLRG1 represents a promising strategy for immunotherapy in patients with CRC.

Background: The prognosis of early unfavorable and advanced stage classic Hodgkin lymphoma (cHL) remains suboptimal with the widely used ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen. Novel agents such as brentuximab vedotin (BV) and anti-PD-1 antibody have demonstrated high efficacy and good tolerance in relapsed/refractory cHL and have also shown promising results in the frontline setting. However, concurrent administration of anti-PD-1 antibody plus AVD in comparison with traditional ABVD regimen alone in untreated classic Hodgkin lymphoma (cHL) has yet to be adequately studied in real-world clinical practice.

Methods: We enrolled eligible adult patients with histologically confirmed cHL who had received initial treatment with the ABVD regimen, or the novel combination regimens of anti-PD1-AVD. The study endpoints included modified progression-free survival (mPFS) and complete response (CR) after 2 cycles of therapy. Propensity score matching (PSM) was performed to balance clinical variables between regimens prior to efficacy comparisons.

Results: Of 172 patients, 137 received the ABVD regimen and 35 received the anti-PD1-AVD regimen. With a median follow-up of 37.7 months, significantly prolonged 3-year modified PFS was reported for anti-PD1-AVD versus ABVD (PSM: 91.0 vs. 61.6%, p = 0.032). Significantly improved CR rate was observed with anti-PD1-AVD versus ABVD (PSM: 86.7 vs. 63.8%, p = 0.049).

Conclusions: In this real-world study, concurrent anti-PD1 antibody with AVD showed significantly prolonged modified PFS and improved CR rate after cycle 2 versus ABVD regimen, supporting the use of novel agents in frontline therapy.

Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches.

Mesothelin (MSLN) is a prominent target antigen for CAR T cell therapy due to its extensive expression in various solid tumors, including pancreatic cancer. However, the therapeutic efficacy of MSLN-targeted CAR T cell therapy has been limited in clinical trials for pancreatic cancer, often resulting in temporary stable disease as the best response. The heterogeneous expression of MSLN and its loss over time, along with the immunosuppressive tumor microenvironment (TME), are key factors restricting effectiveness. Oncolytic viruses are emerging cancer therapies that replicate in tumor cells and remodel the TME into an immunogenic state. Here, we engineered an oncolytic herpes simplex virus type 1 expressing human MSLN (HSV-MSLN) and evaluated its combination with MSLN-CAR T cells in a murine pancreatic ductal adenocarcinoma model. In vitro, HSV-MSLN effectively induced MSLN expression on murine pancreatic cancer cells, with subsequent cell lysis. In co-culture, HSV-MSLN-infected cancer cells activated MSLN-CAR T cells, which effectively eliminated the infected cells. In vivo, HSV-MSLN delivered MSLN on the tumor cell surface and reprogrammed the TME toward an immunogenic state. The combination therapy significantly enhanced antitumor efficacy, inducing activated, proliferative CD8⁺ CAR T cells and reducing PD-1⁺TIM-3⁺ exhausted endogenous CD8⁺ T cells and regulatory T cells in tumors. Furthermore, the combination therapy increased migratory XCR1⁺CD103⁺ dendritic cells (DCs) in tumors and tumor-draining lymph nodes (TDLNs) while expanding CD44⁺CD8⁺ T cells with central and effector memory phenotypes. Taken together, these results demonstrate that HSV-MSLN reprograms immune cells in the TME and TDLNs and synergizes with MSLN-CAR T cells to enhance antitumor responses, leading to a more robust therapeutic effect.