Cancer immunology research最新文献

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.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell-associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.

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.

Tissue-resident memory T (TRM) cells, memory T cells that stably occupy tissues and contribute to immunosurveillance, induce favorable survival outcomes in solid tumors. While TRM cells have been observed in lymph nodes, their phenotype and prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains uncharacterized. In this study, CD103+ T cells were quantified in DLBCL samples by immunofluorescence (IF) staining of tissue biopsies and flow cytometry of cell disaggregates, and linked with clinical outcomes. Across two patient cohorts, CD103+ T cells were identified in both nodal and extranodal DLBCL, and higher CD103+ T cell levels correlated with superior clinical outcomes. Single-cell RNA sequencing (scRNAseq) revealed ITGAE expressing T cells in both malignant and reactive lymph node (rLN) samples. However, transcriptional profiles differed, as a canonical TRM population was observed in the malignant setting. This TRM cluster was enriched for genes associated with cytotoxicity and activation and was validated in an external CITEseq dataset. Flow cytometry additionally confirmed protein expression of TRM markers (CXCR6, CD39, and PD-1) on CD69+CD103+ T cells. We assessed functional activity in co-culture experiments of CD103+ versus CD103- T cells with autologous CD20+ B cells, where CD103+ T cells displayed enhanced killing. CD103+ TRM cells in DLBCL represent a prognostically favorable population with an activated/cytotoxic T cell phenotype.

Tumor-draining lymph nodes are a pivotal site for antitumor T-cell priming. However, their mechanistic roles in cancer immune surveillance and immunotherapy response remain poorly defined. Intratumor (IT) virotherapy generates antitumor T-cell immunity through multifaceted engagement of innate antiviral inflammation. Here we identify type-I interferon (IFN-I) signaling in glioma-draining cervical lymph nodes as a mediator of IT polio virotherapy. Transient IFN-I signaling after IT administration was rescued by cervical perilymphatic infusion (CPLI) virotherapy, targeting cervical lymph nodes directly. Dual-site (IT+CPLI) virotherapy induced profound inflammatory reprogramming of cervical lymph nodes, enhanced viral RNA replication and IFN-I signaling in dendritic cells and high endothelial venules, augmented antiglioma efficacy in mice, and was associated with T-cell activation in patients with recurrent glioblastoma. A Phase 2 clinical trial of IT+CPLI polio virotherapy is ongoing (NCT06177964). This study implicates the lymphatic system as a virotherapy target and demonstrates that CPLI virotherapy has the potential to complement brain tumor immunotherapy.