Cancer immunology research最新文献

Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. Here, we demonstrated that anti-PD-1 treatment regulated cholesterol biosynthesis in cancer cells through the effector cytokine interferon IFN-γ. Mechanistically, IFN-γ-induced IRF1 transcriptionally suppresses the expression of SREBF2, a master regulator of cholesterol synthesis. Reduced cholesterol content inhibited tumor growth and sensitized tumor cells to statins, drugs lowering cholesterol. Overall, our study reveals that IFN-γ-mediated inhibition of cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.

Vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing vaccines to boost adoptively transferred tumour-reactive T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model wherein murine T cells expressing a TCR specific for antigen on syngeneic tumours were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumour-specific T cells with paired vesicular stomatitis virus (VSV) vaccines was associated with robust T cell expansion and delayed tumour progression in the absence of prior lymphodepletion. CAR-T cell expansion and antitumour function was further enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells during vaccination to achieve long-term tumour control.

Adoptive transfer of T lymphocytes specific for tumor-associated neoantigens can elicit immunity against solid tumors in patients. However, how these antigens impact T cell function, effector differentiation, and persistence remains unclear. We examined how an identical CD8+ T cell product was shaped by melanoma expressing either a low-avidity tumor-associated antigen or high-avidity neoantigen, and kinetically profiled T cell differentiation in these two contexts across host tissues. High-avidity neoantigen expression was sufficient to activate naïve CD8+ T cells - leading to robust tumor regression and long-term protective immunity upon tumor rechallenge. Mechanistically, transferred naïve CD8+ T cells reacting to high-avidity neoantigen exhibited enhanced cytokine production, heightened effector function, and sustained persistence compared to the low-avidity wild-type tumors. Antitumor activity to these high-avidity tumors was preserved even in the absence of functional host T and B lymphocytes, and early lymph node trafficking was found to be essential for ACT efficacy. Expanded effector or stem-memory T cells were compared to the naïve pmel-1 T cell product. Stem-memory but not effector-memory cells exhibited similar antitumor efficacy and lymph node trafficking patterns to the naïve cells in mice with high-avidity neoantigen tumors. These findings highlight how differential tumor antigens shape divergent cellular fate and uncover a critical role of T cell trafficking in lymph nodes in shaping high-avidity neoantigen-specific antitumor responses.

Despite advances in cancer immunotherapy, treatment response is still highly variable. One contributing factor is the tumor microenvironment and specifically the presence of suppressive immune cells such as regulatory T (Treg) cells. Being able to target these specifically, while leaving effector T-cell populations untouched, is an attractive strategy that may overcome some of these issues, improving responses. To generate antibodies specific for tumor-associated Tregs, lymphocytes were isolated from tumor-bearing mice and panned against the n-CoDeR phage antibody library. Using the target-agnostic F.I.R.S.T. discovery platform, they were evaluated in ex vivo and in vivo models to determine tissue and cell selectivity and specificity and ability to deplete Tregs and elicit tumor control in subcutaneous tumor models. A total of 24 antibodies were identified and explored, representing a range of specificities from pan-T cell to Treg and tumor Treg specific. Relative expression/binding of these mAbs on tumor Tregs was not a predictor of subsequent Treg deletion efficacy or tumor control, whereas tumor Treg selectivity was. One mAb in particular demonstrated tumor-specific depletion of Tregs, leaving those in the spleen and blood untouched. This Fc:FcγR-mediated tumor-specific Treg depletion was important for antitumor effects. Target deconvolution showed that this mAb binds a distinct epitope within ICAM-1, which is hypothesized to mediate its selectivity toward tumor Tregs. These data validate the target-agnostic discovery approach as a viable means to identify new therapeutic antibodies.

Liver metastases are associated with poor cancer outcomes in many solid malignancies, but the factors influencing the trajectory of patients with liver metastases are poorly defined. It is known that liver metastases suppress systemic antitumor immunity; however, the underlying mechanisms remain incompletely described. We report that liver metastases promote disease progression in patients and preclinical models. Patients with liver metastases progress rapidly, regardless of primary tumor type. In multiple murine models, we find that liver metastases potentiate neutrophil migration and activity. Neutrophils licensed by liver metastasis augment metastatic colonization in an IL1-dependent manner. Thus, liver metastasis rewires systemic immunity to promote cancer progression. This work has implications for treatment strategies to address the poor clinical outcomes associated with liver metastasis.

Current histopathologic classifications do not reliably distinguish patients with primary cutaneous squamous cell carcinomas (cSCC) at risk of relapse from those with nonrelapsing tumors. This underscores the need for molecular signatures capable of stratifying patients during primary tumor resection. In this study, we used high-dimensional imaging mass cytometry and a 39-antibody panel to define the immune landscape of 20 primary cSCC with distinct clinical outcomes, four relapsing cSCC, and their perilesional skins. Computational analysis of spatially resolved single-cell data from 47 imaging mass cytometry images identified 12 immune-cell subsets that discriminated primary cSCC from perilesional skin. Regulatory T cells, cytotoxic CD8+ T lymphocytes, and tumor-associated macrophages and neutrophils characterized tumors, whereas Langerhans cells and skin-resident macrophages defined perilesional skin. Skin-resident macrophages were characterized by the expression of CD206, CD11c, and HLA-DR and the absence of CD14. These cells infiltrated tumors from nonrelapsing patients more efficiently. We found a higher density of proliferating, mature, and cytotoxic cells within this macrophage subset, consistent with the absence of relapse. Spectral flow cytometry analysis on fresh tumor biopsies revealed that the skin-resident macrophages had phagocytic properties, suggesting a role in tumor antigen processing. Additionally, neighborhood profiling revealed that DC-LAMP+ dendritic cells were in close proximity with helper and cytotoxic T lymphocytes in primary cSCC from patients without relapse, indicative of active adaptive immunity. Our findings identify phagocytic skin-resident macrophages and dendritic cell-T cell clusters as features differentiating nonrelapsing cSCC from primary cSCC at risk of relapse. These data have the potential to guide the identification of prognostic biomarkers for cSCC.

The immunosuppressive tumor microenvironment remains a major barrier to effective immunotherapy in gastric cancer. In this study, we identified the E3 ubiquitin ligase BFAR as a critical regulator of neutrophil-mediated immune evasion through the S100A8/A9-BFAR-PRP19-YBX1 signaling axis. Multiomics analyses revealed that BFAR is overexpressed in gastric cancer and correlates with poor prognosis. Functional studies demonstrated that BFAR knockdown suppressed tumor growth by reducing neutrophil infiltration and immunosuppressive reprogramming to restore CD8+ T-cell function. Mechanistically, BFAR mediated K48-linked ubiquitination and degradation of PRP19, leading to stabilization of the oncoprotein YBX1, which transcriptionally upregulated neutrophil-recruiting chemokines CXCL1/CXCL3. Infiltrating neutrophils secreted S100A8/A9, which activated NF-κB to induce BFAR expression in tumor cells and created a feed-forward loop that sustains an immunosuppressive tumor microenvironment. Furthermore, BFAR promoted neutrophil PD-L1 expression via GM-CSF, reinforcing T-cell exhaustion. Clinically, BFAR expression correlated with neutrophil infiltration and poor response to anti-PD-1 therapy, whereas its inhibition synergizes with immune checkpoint blockade in preclinical models. Our work unveils BFAR as a central orchestrator of neutrophil-driven immunosuppression and proposes targeting this axis to enhance immunotherapy efficacy in gastric cancer.

Immune checkpoint blockade for the treatment of malignancies has been focused on reversing inhibitory pathways in T lymphocytes. NK cells are a potent innate defense against tumors and virally infected cells, but their therapeutic manipulation for anticancer immunity has been inadequately explored. Considerable attention has been focused on approaches to blocking inhibitory receptors on NK and myeloid cells. Most effort has been directed to the killer immunoglobulin-like receptors and CD94/NKG2A on NK cells. Another set of receptors with similar function in both NK cells and myeloid cells is the leukocyte immunoglobulin-like receptors (LILR) that interact with a wide variety of HLA molecules. Using pan-anti-HLA mAbs that recognize a conserved epitopic region on HLA also seen by LILRs, we investigated their functional effects in several models of tumor immunity. The pan-anti-HLA mAbs blocked the binding of most LILRs and did not block killer cell immunoglobulin-like receptors or CD94/NKG2A/C or T-cell receptor recognition. They also activated dysfunctional NK cells explanted from a variety of human cancers and resulted in enhancement of tumor immunity in humanized mice. The mAbs also exert direct antitumor effects. These results suggest that activation of innate immunity via disruption of HLA/LILR interactions is a potent approach for control of both primary tumors and potentially tumor metastases.

Polymerase epsilon-mutant (POLE-mut) endometrial cancers are characterized by a near 100% disease-specific survival rate, even when treated with surgery alone. This survival, combined with the ultramutated genome and high level of neoantigens in these tumors, indicates a substantial degree of immune control in preventing disease spread and recurrence. Although these features are intriguing, the analysis of immune infiltration in POLE-mut endometrial cancers has predominantly been confined to IHC studies. In this study, we used single-cell RNA and T-cell receptor sequencing to characterize the immune landscape of POLE-mut endometrial cancers. Moreover, we analyzed patient blood samples taken 2 to 8 years after curative treatment to assess the formation of long-term immune memory in circulation. We identified specialized tumor-infiltrating myeloid subsets at different stages of maturation, an array of lymphocytes ranging from immature to cytotoxic, and adaptive NK cells, as well as tumor-reactive exhausted and effector T cells, all contributing to a highly inflammatory antitumor response. Our analysis of blood samples taken years after curative treatment uncovered the presence of tumor-reactive T-cell clones that matched the primary tumor. This indicates the formation of systemic long-term memory immune responses in POLE-mut endometrial cancer survivors. Our study highlights the distinctive immunogenicity of POLE-mut endometrial cancer and identifies key features associated with persistent antitumor immunity that may contribute to prolonged, relapse-free survival.