Cancer immunology research最新文献

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.

Reinvigoration of tumor-reactive T cells using costimulatory bispecific antibodies (bsAb) targeting CD28 is emerging as a promising therapeutic strategy. Conditional, tumor-specific recruitment can offer a layer of control and specificity. We developed pH-selective CD28xV-domain Ig-containing suppressor of T-cell activation (VISTA) bsAbs to act specifically within the acidic tumor microenvironment, aiming for enhanced T cell-mediated cancer cell killing while minimizing systemic T-cell activation and cytokine release syndrome risk. CD28 agonism by our CD28xVISTA bsAbs relies on pH-selective engagement of VISTA, a protein robustly expressed on myeloid cells abundant in most solid tumors. Our lead candidate displayed pH-dependent engagement of VISTA and simultaneous binding to CD28, resulting in VISTA-dependent CD28 signaling in a reporter cell line. CD28xVISTA avidly binds VISTA+ cells, and costimulatory activity was shown in vitro by its ability to activate and expand T cells and enhance T cell-mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells in the presence of a tumor-associated antigen-targeted anti-CD3 T-cell engager. This CD28xVISTA bsAb efficiently inhibited the growth of human VISTA-expressing MC38 tumors in a humanized CD28 syngeneic mouse model in combination with PD-1 blockade. Our findings support signaling both in cis (between T cell and target cell displaying peptide-MHC complex) and in trans, with stimulation occurring through CD28 clustering outside of the immune synapse. This CD28xVISTA bsAb showed no signs of superagonistic properties in several in vitro cytokine release syndrome assays. Thus, our data support clinical development for solid tumors in combination with anti-PD-1 or tumor-associated antigen-targeted anti-CD3 T-cell engagers.

Although immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model with P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti-PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade-based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. In this study, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 are associated with a positive antitumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and nonresponding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHCIIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of nonresponding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte-to-macrophage differentiation route may hamper the response to immune checkpoint blockade. These insights will direct future research toward a temporal analysis of tumor-associated macrophages, aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way for novel strategies to enhance the efficacy of PD-1 blockade.

Tumor-associated macrophages (TAM) display remarkable functional heterogeneity, yet the molecular mechanisms driving their diverse phenotypes remain elusive. Using CRISPR screens in primary macrophages, we identified tumor-derived factors, including lactic acid, prostaglandin E2, and GM-CSF, as key modulators of TAM polarization. These factors interacted cooperatively and antagonistically to shape distinct TAM phenotypes that were highly conserved across human cancers. Mechanistically, lactic acid and PGE2 jointly induced angiogenic gene programs while suppressing GM-CSF-driven MHC-II expression at the chromatin level, creating mutually exclusive distributions of proangiogenic and MHC-II+ TAMs, which were differentially localized to specific spatial niches in the tumor microenvironment. Furthermore, we showed that shifting TAMs to an interferon-responsive phenotype, triggered by Adar inactivation, significantly promoted the infiltration of effector CD8+ T cells through specific receptor-ligand interactions. These findings uncover a conserved mechanism of TAM polarization and offer insights into therapeutic strategies for TAM reprogramming to potentiate cancer immunotherapy.

Despite recent progress within the field of immuno-oncology, immune suppression in the tumor microenvironment, defective antigen presentation, and low levels of tumor-specific T cells are key limitations of current cancer immunotherapies. CD40-targeting immunotherapies hold promise for addressing these limitations across solid tumors. In this study, we describe ATOR-4066, a bispecific antibody that targets CD40 and CEACAM5, developed using the Neo-X-Prime platform. ATOR-4066 showed potent CEACAM5-dependent activation in vitro, with an ability to activate intratumoral immune cells from patient-derived material. In vivo, ATOR-4066 induced superior antitumor activity compared with a CD40 mAb in MC38-carcinoembryonic antigen tumors and cured mice with well-established tumors with heterogeneous CEACAM5 expression. Using RNA sequencing, flow cytometry, and cytokine analysis, we showed that ATOR-4066 promoted immune cell trafficking to tumors and activated both myeloid cells and T cells within the tumor microenvironment, with limited immune activation in the periphery. ATOR-4066 initially induced a T cell-independent antitumor response, yet we found that a functional T-cell response was critical for long-term tumor control and immunity directed to tumor antigens other than CEACAM5. Finally, we demonstrated that ATOR-4066 synergized with PD-1 blockade in vitro. In conclusion, these data provide mechanistic evidence for the proposed mode of action and support further development of ATOR-4066 in CEACAM5-expressing cancers.

NK cell licensing is an educational process that enhances responsiveness to activating signals in maturing NK cells and is predominantly regulated by MHC class I-specific inhibitory signals. However, the role of non-MHC signaling in this process remains unclear. In this study, we investigated the role of FcRγ, an adaptor protein associated with activating receptors, in the regulation of NK cell responsiveness. We showed that although FcRγ does not affect NK cell development, maturation, or cytotoxic molecule expression, FcRγ-deficient (Fcer1g-/-) NK cells exhibit hyporesponsiveness to tumor cells and impaired tumor control in vivo. Transcriptional and proteomic analyses revealed significantly reduced expression of CD244 in Fcer1g-/- NK cells, which contributed to their functional maturation and licensing, suggesting an additional, nonredundant pathway of NK cell education. Pretreatment with common γ-chain cytokines (IL2 or IL15) rescued Fcer1g-/- NK cells from hyporesponsiveness and restored their antitumor activity. These findings demonstrate that FcRγ plays a crucial role in licensing NK cells for antitumor immune responses through CD244 signaling and that γ-chain cytokines can override the absence of this signaling.

Endometrial cancer is the sixth most common cancer in women worldwide and the fourth most common cancer in women in the United States. In the United States, its incidence and mortality rates have continued to increase since the late 1990s. Endometrial cancer comprises most uterine corpus carcinomas and represents a heterogeneous group of cancers varying in pathology, histology, molecular biology, immunogenicity, and prognosis. Recently, the advancement of molecular classification and subsequent clinical trials have led to new FDA approvals for the use of immune checkpoint inhibitors in endometrial cancer. However, recurrent and advanced-stage endometrial cancer continues to demonstrate high morbidity and mortality, denoting an unmet need for innovative immunotherapeutic strategies. This review explores current concepts in the endometrial cancer tumor immune microenvironment, comparing antigenicity, immunosurveillance, and immunoregulation among molecular and histologic subtypes and providing insight into which subtypes may be particularly responsive to immunotherapy. Novel immunotherapeutic strategies targeting cancer antigens, emerging immune checkpoints, immunomodulatory cytokines, and tumor-infiltrating immune cells are described, and corresponding clinical trials are presented. Integrated approaches such as immunogenic modulation, which enhances tumor susceptibility to immune attack, and immune subset conditioning, which modifies suppressive immune components within the tumor immune microenvironment, are presented as promising avenues to render "cold" tumors responsive. Together, the immunotherapies reviewed here offer potential strategies for treating patients with advanced or refractory endometrial cancer.

Treatment of melanoma with BRAF inhibitors plus MEK inhibitors (BRAFi + MEKi) stimulates an intratumoral immune response, in part through pyroptosis mediated by the pore-forming protein gasdermin E (GSDME/Gsdme). How GSDME mediates effects on tumoral immunity is not well characterized. Using single-cell RNA-sequencing (scRNA-seq) and flow cytometry in BRAFi + MEKi treated melanoma, we show herein that isogenic Gsdme knockout (KO) tumors show decreased infiltration with T cells, natural killer (NK) cells and regulatory T cells (Tregs) compared to control tumors. Infiltrated Tregs in Gsdme KO tumors displayed decreased expression of the interleukin 2 receptor and phenotypic markers associated with suppressive function. Furthermore, intratumoral, the frequency of phenotypically suppressive Tregs were decreased after BRAFi + MEKi treatment in Gsdme KO tumors engineered to express a pyroptosis-defective mutant form of Gsdme (T6E) compared to Gsdme KO tumors engineered to re-express wild-type Gsdme. Combining BRAFi + MEKi with a TLR9 agonist limited regrowth of Gsdme-deficient tumors, and this was associated with a further reduction in intratumoral Tregs. Overall, we show a critical role of GSDME in the modulation of intratumoral immune cells in BRAFi + MEKi-treated melanoma.