Oncoimmunology最新文献

Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied in situ in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.

Therapeutic immunization against tumor neoantigens has the potential to induce potent and highly selective CD8⁺ T-cell-mediated antitumor immunity. Consequently, immunization strategies that generate robust neoantigen-specific T-cell responses are needed. Here, we tested homologous and heterologous DNA- and peptide-based immunization strategies using a neoantigen model. We observed that priming with DNA followed by peptide boost immunization elicited the strongest CD8⁺ T-cell responses, which exhibited effector and memory precursor phenotypes and led to the formation of circulating and skin-resident memory T cells. In prophylactic settings, this immunization regimen delayed the growth of B16F10 melanoma and rejected EL4 lymphoma cells expressing a self-antigen. In a therapeutic setting, a DNA prime-peptide boost eliminated EL4 tumors expressing the neo-epitope model in most mice. Consistently, DNA prime-peptide boost targeting two bona fide neoepitopes of MC38 tumor model elicited neoepitope-specific CD8⁺ T-cell responses and a marked therapeutic effect, which may be enhanced by combining with anti-PD-1 antibody. These results highlight the potential of DNA prime-peptide boost as a promising strategy for therapeutic neoantigen immunization that elicits strong CD8⁺ T-cell responses and potent antitumor effects.

Interleukin (IL)-37 is one of the "youngest" IL-1 family members and one of the few molecules exerting anti-inflammatory activity. Upon inflammasome activation, the cytokine precursor is converted into its mature form, which acts intracellularly as a nuclear transcription factor, impairing the production of pro-inflammatory cytokines, and extracellularly by forming the IL-37/IL-18Rα/IL-1R8 complex, favoring IL-1R8 inhibitory signaling with immunosuppressive function. IL-1R8, which is mostly expressed in a number of cell types, negatively regulates both IL-1R/TLR signaling, blocking the NF-kB/JNK pathway and the production of pro-inflammatory cytokines. Owing to its ability to inhibit both innate and adaptive immunity, IL-37 has been reported to control inflammation in many chronic disorders, including cancer. IL-37 impairs the proliferation and migration of tumor cells, mediates anti-angiogenetic mechanisms, and favors immunoregulation in the tumor microenvironment (TME). This review aims to provide a current overview of IL-37 genetic and biological features and of its active interaction with IL-1R8, inducing anti-inflammatory effects on the immune system and affecting cancer cell dynamics in the TME. Moreover, it analyzes the rare pro-tumoral effects of IL-37 in some tumors and discusses their possible mechanisms. It concludes that, due to its strong anti-inflammatory property, IL-37 can be considered a potential regulator in the pathogenesis of a variety of cancers, slowing tumor progression through multiple pathways and providing valuable information for tumor immune target therapy.

Combining radiotherapy with immune checkpoint inhibitors (RT-ICI) triggers systemic antitumor responses, such as abscopal effects (AbE). Predictors of AbE and its impact on survival in real-world settings remain poorly defined. This multicenter, retrospective cohort study assessed the prevalence of AbE in ICI-refractory progressive metastatic patients by evaluating the additive effect of RT on nonirradiated lesions (NIL). We screened 3773 cases to identify patients with stage IV tumors receiving RT during/after ICI. Abscopal benefit (AB) was defined as abscopal response (AR) or control (AC) by measuring NILs according to iRECIST. AB was observed in 61.3% of 142 included patients and associated with improved median overall survival (18 vs. 8 months, p < 0.01) and progression-free survival (7 vs. 3 months, p < 0.01). Logistic regression identified younger age (OR = 0.951, 95% CI: 0.903-0.995, p = 0.039) and longer ICI-RT intervals (OR = 1.077, 95% CI: 1.019-1.171, p = 0.027) as predictors of AB. There was no association between radiation dose or tumor volume and AB. Cox regression identified BMI ≥ 25 kg/m² (HR = 3.348, 95% CI: 1.557-7.202, p = 0.002) and CRP ≥ 5 mg/l (HR = 3.058, 95% CI: 1.211-7.724, p = 0.016) as independent negative prognostic factors for survival in this RT-ICI cohort. Median survival was significantly higher among patients receiving ultrahypofractionated RT, compared to other fractions (21 vs. 11 months; p = 0.024). AbE seems to occur reliably and is prognostically relevant in ICI-refractory patients receiving RT. Patient- and timing-related factors were more predictive than RT details in our cohort. Our findings enhance the understanding of tailored RT-ICI approaches and lay the groundwork for targeted radioimmunotherapy strategies and personalized clinical trial designs.

Liver X receptor β (LXRβ) is a key transcription factor involved in lipid metabolism and immune regulation, yet its functional role in tumor-infiltrating T cells remains largely unresolved. While LXRβ has been shown to suppress NF-κB target gene expression, the mechanistic interaction between LXRβ and NF-κB signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXRβ as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors. LXRβ overexpression altered the transcriptional and phenotypic landscape of CAR-T cells, including the modulation of stem-like TCF1⁺ populations, proliferative capacity (Ki-67), and cytokine production (IFNγ, TNFα). Through genetic perturbation of NF-κB components, particularly RelB, we further demonstrate that disrupting non-canonical NF-κB signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation. Notably, combined targeting of LXRβ and RelB produced additive and, in some settings, synergistic benefits, improving metabolic fitness, reducing terminal exhaustion, and augmenting anti-tumor activity in vivo. Together, these findings define an LXRβ-NF-κB regulatory axis that shapes CAR-T cell fate and function in the TME and highlight this pathway as a promising target for improving CAR-T cell-based therapies against solid tumors.

The immunomodulatory potential of radiotherapy provides a strong rationale for its combination with immunotherapies and other immunostimulatory agents. However, current combinations yield suboptimal clinical benefits. As the mechanisms behind radiotherapy-induced immunomodulation are gradually unraveled, various key factors have been identified as critical modulators of this process, opening new possibilities for adapting radiotherapy to immunotherapy. Here, we discuss seven factors: dose‒fractionation regimens of radiotherapy (RT), sequence and timing of RT and immunotherapy, radiation field, type of ionizing radiation, normal tissue effects, choice of the lesion to irradiate and identification of biomarkers. Preclinical and clinical studies on the combination of immunotherapy and radiotherapy are discussed, novel immunotherapeutic approaches are highlighted and improvements in study design are suggested.

Glioblastoma (GBM) is the most common primary central nervous system tumor with a dismal prognosis and limited treatment options. Recent success utilizing immunotherapies for treating other solid tumors have been largely unsuccessful in GBM. One of the primary mechanisms of GBM immunotherapeutic resistance is because of excessive infiltration of myeloid cells that create an immunosuppressive tumor microenvironment (TME). Among these infiltrating myeloid cells, tumor-associated macrophages (TAMs), comprise a substantial portion of the TME and are associated with poor prognosis in GBM patients. Researchers have only recently begun to dissect the dynamics and complexity of TAMs. However, reliable and reproducible translational methods for generating GBM TAMs in vitro are lacking. Here, we have investigated an in vitro, reproducible murine-based model for bone marrow-derived, glioma-educated macrophages (gTAMs) and performed rigorous analysis to expand our understanding of gTAMs to provide a validated tool for investigating therapeutic response.

Interleukin (IL)-1β is known to promote lung cancer growth in both humans and mice. However, in the context of the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, IL-1β can overcome resistance.

Bispecific antibodies are used for the treatment of hematological malignancies as well as solid tumors. One of their main effector mechanisms is the recruitment of effector cells such as CD8⁺ T cells and CD16A⁺ NK cells to tumor cells. Bispecific innate cell engagers (ICE®) harnessing CD16A⁺ NK cells have been shown to induce significant tumor cell lysis in preclinical models, translating to promising signs of clinical activity together with a well-managed safety profile. However, how killing of tumor cells by NK cells influences other innate immune cells in the tumor microenvironment, such as dendritic cells (DCs), instrumental in bridging innate and adaptive tumor immunity, is largely unknown. Thus, we here analyzed whether antibody-dependent cell-mediated cytotoxicity by NK cells affected human DC subpopulations. We could show that killing of tumor cells leads to a strong activation of human conventional DCs type 1 (cDC1), DC2, and DC3 with enhanced expression of co-stimulatory molecules as well as the secretion of proinflammatory cytokines. Further, DC subpopulations as well as surviving tumor cells showed increased expression of the immunoregulatory molecule PD-L1 that is known to dampen T-cell immunity. Nevertheless, ADCC boosted the capacity of cDC1 and DC2 to prime naïve T cell responses but not of DC3. Thus, our data suggests that the therapy with bispecific antibodies targeting NK cells may have the potential to facilitate adaptive antitumor immune responses via activation of cDC1 and DC2.

Breast cancer is genetically and histologically heterogenous, and is influenced by a variety of factors, including the tumor microenvironment (TME). The PAM50 subtypes; Luminal A, Luminal B, Normal-like, Basal-like and Her2-enriched, are associated with different tumor phenotypes and overall survival. The quantity and quality of immune cell infiltration in breast tumors play a key role in cancer development and progression and are associated with survival and treatment response. We used multiplex immunohistochemistry, single-cell RNA sequencing, and two deconvolution algorithms to explore the immune landscape across PAM50 subtypes. Immunostaining of CD3⁺ T cells, tryptase⁺ mast cells, CD20⁺ B cells, CD68⁺ CD163⁺ macrophages, and CD66b⁺ granulocytes revealed marked differences in tumor immune infiltrates according to breast cancer subtypes. Luminal tumors were relatively deprived of T cells and B cells, while exhibiting sparse to moderate amounts of macrophage infiltration. In contrast, Her2-enriched tumors exhibited a moderate immune presence, with sparse to moderate T cell infiltration and moderate infiltration of B cells and macrophages. At the other end of the spectrum, Basal-like tumors stood out for their strikingly rich immune environment and are heavily infiltrated by T cells, B cells, and macrophages. The results from the single-cell and deconvolution analyses confirmed subtype-specific immune microenvironments, which also allowed us to observe increased levels of natural killer (NK) and CD8⁺ T cells in Her2-enriched and Basal-like subtypes. In conclusion, our findings demonstrate significant differences in the immune tumor microenvironment between the established breast cancer molecular subtypes.