Journal for Immunotherapy of Cancer最新文献

Adoptive cell therapy (ACT) has demonstrated curative potential in select cancers, but its translation to solid tumors such as ovarian cancer (OC) has been hindered by multiple factors, including tumor heterogeneity, immune exclusion, and a profoundly immunosuppressive tumor microenvironment. This review provides a comprehensive analysis of current ACT modalities, including tumor-infiltrating lymphocytes, T cell receptor-engineered, and chimeric antigen receptor-T cell therapies, as well as emerging approaches such as bispecific T cell engager (BiTE)-secreting T cells, dual-targeting platforms, and synthetic antigen receptors. We examine their application in OC and contextualize relevant findings using insights from other solid tumors. Key barriers, including limited T cell persistence, antigen escape, and T cell exhaustion, are explored alongside strategies to enhance efficacy through cytokine armoring, checkpoint modulation, metabolic reprogramming, and gene editing. We further highlight innovations in safety engineering, including logic-gated and self-regulating synthetic circuits, to mitigate toxicity and improve precision. Additional attention is given to the evolving role of allogeneic products and in vivo engineering as scalable solutions. Finally, we emphasize the critical value of integrating high-dimensional tools such as spatial transcriptomics, single-cell profiling, and machine learning to refine ACT design, identify biomarkers of response, and support patient selection and stratification. Collectively, these advances offer a roadmap for overcoming the unique immunologic barriers to ACT in OC and accelerating the development of more potent, durable, and personalized T cell-based strategies.

Peptide presentation on human leukocyte antigens (HLAs) is essential for initiating T-cell responses and all consequences of this presentation including anticancer immunity or immune escape. Many studies have relied on in silico prediction tools rather than biological measurement of HLA presentation to study these effects. To better assess the frequency and consequences of neoantigen presentation, we overexpressed 125 combinations of full-length neoantigens and one HLA class I allele to experimentally validate presentation of mutated and non-mutated HLA ligands through HLA ligand isolation followed by tandem mass spectrometry. A successful presentation was observed only in 22% of predicted cases with strong implications on previously described downstream effects. For example, the association of HLA loss of heterozygosity with predicted neoepitopes was challenged for 58% (73/125) of combinations. Furthermore, when testing 51 sequences used for personalized messenger RNA neoepitope vaccines, we observed that clinical responses were independent of the presentation status of the neoepitopes. Even a presumably neoepitope-specific and strongly expanded T cell receptor clone from a neoantigen vaccination study could not be linked to a successfully presented neoepitope. Overall, these data highlight the importance of validating the presentation of neoepitopes to fully understand our interpretation of clinical mutation-specific responses and their related effects, including immune evasion.

Background: Oncolytic herpes simplex virus (oHSV) therapy is a live virus-based immunotherapy that lyses tumor cells which release antigens and activate antitumor immunity. oHSV therapy has been shown to increase ATP production and release of extracellular ATP (eATP). In the extracellular tumor microenvironment, eATP functions as an immune-activating damage-associated molecular pattern but is hydrolyzed to extracellular adenosine (eADO), which can be immune-suppressive. eADO is generated by the sequential action of ectoenzymes CD39 and CD73 (NT5E). Here, we examined the role of immunosuppressive eADO signaling in regulating antitumor immune efficacy of oHSV.

Methods: We evaluated changes in eADO signaling in vitro and in patient specimens after virotherapy. A genetic CD73 knock-out mouse model and blocking antibodies were used to assess the impact of CD73 on virotherapy in two different solid tumor models. Single-cell RNA sequencing was employed to assess changes in immune cell infiltration and communication. Flow cytometric immunophenotyping and immunofluorescent imaging were utilized to confirm single-cell sequencing predicted changes in tumor microenvironment.

Results: Transcriptomic analysis of patient tumors pre-virotherapy and post-virotherapy with CAN-3110 revealed increased expression of the adenosine receptor gene ADORA2B after treatment. High NT5E gene expression, as well as gene signatures suggestive of adenosine signaling, correlated with a significantly worse prognosis for patients with solid tumors. Single-cell sequencing of immune cells recruited to tumor-bearing brain hemispheres in CD73 knockout mice revealed an increase in macrophage-mediated antigen presentation and CD4⁺ T cell cross-communication. Intracranial tumor-bearing CD73 knock-out mice treated with oHSV showed significant therapeutic improvement as the result of oHSV compared with wild-type mice. Combination of virotherapy with CD73 antibody blockade also resulted in enhanced antitumor efficacy.

Conclusions: Here, we identify that immunosuppressive eADO signaling in the TME is a major barrier to oHSV therapy and CD73 blockade prevents tumor immune escape. The combination of oHSV with CD73 blockade supports the development of an antitumor immune memory response in solid tumors. This study supports clinical development of this combination strategy.

Shared tumor-associated antigen (TAA) vaccines are the legacy of several generations of cancer immunologists who have labored to bring them to patients with cancer to improve their disease outcome and eventually use them to prevent cancer. TAA vaccines failed as monotherapy but the development of checkpoint inhibitors and other reagents that can modify immunosuppressive tumor microenvironment, warrants their reassessment in combination immunotherapy trials. They now sit on shelves and in freezers of academic labs and pharmaceutical companies, but if shown effective in the new setting, could be quickly turned into broadly applicable, inexpensive, off-the-shelf vaccines. Shared TAA vaccines also provide a unique opportunity to address the global cancer pandemic by repurposing them for cancer prevention. The opportunity that shared TAA vaccines provide to help patients now and to protect millions globally from the agony of cancer diagnosis in the future, is either not fully recognized, recognized but ignored, or at best, being put on hold.

Background: Mismatch repair deficiency (dMMR) colorectal cancer (CRC) is characterized by abundant tumor-infiltrating lymphocytes and tertiary lymphoid structures (TLSs). However, while B cells are pivotal for TLS formation, their function and the signaling pathways driving their activation in dMMR CRCs remain undefined.

Methods: Data from The Cancer Genome Atlas (TCGA) database analyzed by XCELL method and multiplex immunofluorescence (MIF) staining tissue slides were used to compare the abundance and distribution of TLSs and B cell populations between dMMR and proficient MMR cohorts. Then MLH1 knockdown models both in vitro and in vivo were used to mimic dMMR/high microsatellite instability (MSI-H) tumors and explore the influence of tumor cells on B cell behavior.

Results: TCGA analysis and MIF staining revealed a significant association between memory B cell abundance, TLS formation, and improved prognosis in dMMR CRCs. In vivo MLH1 knockdown models showed that B cell depletion enhanced tumor growth and reduced the efficacy of anti-PD-1 treatment in dMMR CRCs. Furthermore, in vitro experiments demonstrated a dsDNA/STING/type I interferon (IFN)/STAT1/ccl19 signaling pathway mediating the dMMR-induced increase in memory B cells.

Conclusions: In conclusion, these findings show that CCL19 generated by STING/type I IFN/STAT1 pathway in dMMR/MSI-H CRC cells can promote the expansion of memory B cells, which suppresses tumor growth and enhances the efficacy of PD-1 blockade.

Tumor-infiltrating microbes are emerging as a novel dimension of cancer biology, with growing evidence suggesting their potential as prognostic and predictive biomarkers. In this issue, Chen et al demonstrate associations between microbial signatures and treatment response in triple-negative breast cancer (TNBC). They join a growing list of examples whereby tumor-infiltrating microbes influence therapeutic efficacy, with mechanisms ranging from drug metabolism to immune modulation. Here, we explore the known mechanisms, as well as the methodological and conceptual challenges facing microbial biomarker research, including contamination risk, detection sensitivity, and the functional validation of microbial activity. As the field advances, integrating microbial profiling with genomic and immunological data, alongside foundational microbiological techniques, will be essential to clarify the role of microbes in cancer progression and treatment response. Ultimately, a deeper understanding of these microbial ecosystems may open new avenues for precision oncology in TNBC and beyond.

Patients with metastatic breast cancer (MBC) have limited opportunities for a cure, as they develop resistance to therapies and continually form new metastases. Clinical overt metastases emerge from metastasis-initiating cancer cells (MICs) that disseminate during breast cancer (BC) progression. Currently, there are no available therapies that inhibit MIC dissemination to prevent overt metastasis. We provide preclinical evidence that intratumoral (IT) delivery of type I polarized dendritic cells (DC1) limited the MIC dissemination mechanisms in tumor lesions of human epidermal growth factor receptor 2 (HER2)+ mammary carcinoma. Interferon gamma, a prominent cytokine secreted by T helper 1 and innate-like immune effector cells, inhibited dissemination of MICs from the tumor lesions via the modulation of HER2/progesterone receptor/Wnt family member 4/receptor activator of nuclear factor kappa beta ligand signaling. Importantly, we provide clinical evidence that in patients with stage I-III HER2+ BC, there was significant regression of the primary tumor treated with IT DC1, as well as inhibition of disseminating MIC phenotypes. We observed a reduced burden of MICs in the bone marrow (BM) of patients with stage I-III HER2+BC treated with IT DC1, compared with untreated patients and those treated with standard neoadjuvant HER2 therapies paclitaxel, with or without carboplatin, trastuzumab and pertuzumab (Taxol, Carboplatin, Herceptin and Perjeta or THP). We also treated a single patient with de novo stage IV HER2+ MBC with trastuzumab, pertuzumab and tamoxifen in combination with IT DC1. Remarkably, this treatment resulted in near-complete regression of primary tumor and metastatic disease, along with inhibition of MIC seeding in the BM. These findings suggest an intriguing strategy to inhibit the dissemination of MICs and prevent further overt metastasis in all patients with BC.

Background: The immunonutritional background has been deeply implicated in cancer behavior and clinical outcomes. In this study, we explored the prognostic impact of the Controlling Nutritional Status (CONUT) score through its correlation with blood immunophenotypes and cytokines to provide an easily available non-invasive tool to predict the survival benefit from first-line immune checkpoint inhibitors±chemotherapy (ICI±CHT) in patients affected by advanced non-small cell lung cancer (aNSCLC).

Material and methods: From a prospective cohort of patients with aNSCLC treated with first-line ICI±CHT, clinicopathological data and baseline blood samples for the assessment of CONUT score (albumin, lymphocytes, total cholesterol), relevant immunophenotypes (flow cytometry) and cytokines (multiplex array) were collected. Correlations of CONUT score with survival outcomes (progression-free/overall survival [PFS/OS]) and circulating immune-inflammatory benchmarks were analyzed.

Results: Among 178 patients enrolled in the AIRC (Italian Association for Cancer Research) project, 153 received ICI±CHT as first-line. Nutritional status tested by CONUT score was available in 137 cases and was <3, meaning good nutritional status, in 77 (56.2%), whereas scored ≥3 in 60 (43.8%), meaning an impaired nutritional status. At a median follow-up of 27.4 months (95% CI 22.9 to 32.0), patients with a CONUT score <3, compared to those with CONUT score ≥3, experienced significantly longer PFS (median PFS 8.03 vs 3.88 months, HR 0.58, 95% CI 0.40 to 0.84, p=0.004) and OS (median OS 22.24 vs 8.75 months, HR 0.61, 95% CI 0.40 to 0.94, p=0.03). The multivariable analysis, adjusting for age, histology, metastatic sites, sex, programmed death-ligand 1 (PD-L1), Eastern Cooperative Oncology Group Performance Status and treatment type, confirmed the prognostic impact of CONUT score in terms of PFS (HR 0.61, 95% CI 0.41 to 0.93, p=0.02) and OS (HR 0.60, 95% CI 0.38 to 0.96 p=0.03). Patients with CONUT score ≥3 displayed significantly higher blood levels of interleukin (IL)-1β, IL-12, IL-10, interferon-γ, IL-6, and soluble PD-L1 compared with those with CONUT score <3. A higher fraction of CD14+ cells (p=0.01) and CD8+Ki67+ (p<0.001) lymphocytes also characterized the blood of patients with CONUT score ≥3 compared with those with CONUT score <3.

Conclusion: A baseline good nutritional status (CONUT score <3) is associated with a distinct circulating immune-inflammatory profile and correlates with improved clinical outcomes in patients with aNSCLC treated with first-line ICI±CHT.

Background: Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.

Methods: The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed Apc^min/+ mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.

Results: Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed Apc^min/+ mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBPβ synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.

Conclusion: Our findings reveal EEF1B2-mediated C/EBPβ protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.