Huang YH, Wu SY, Lee CT
… +8 more, Chung BS, Lin PC, Chan RH, Chen PC, Lin BW, Shen MR, Chen SH, Yeh YM
Cancer Immunol Immunother
· 2026 Mar · PMID 41774207
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BACKGROUND: Lymphocyte-activation gene 3 (LAG3), an inhibitory immune checkpoint receptor, has emerged as a potential therapeutic target in various cancer, including colorectal cancer (CRC). However, its prognostic role...BACKGROUND: Lymphocyte-activation gene 3 (LAG3), an inhibitory immune checkpoint receptor, has emerged as a potential therapeutic target in various cancer, including colorectal cancer (CRC). However, its prognostic role and immunologic context in metastatic CRC (mCRC) remain unclear. This study investigated the prognostic impact of LAG3 expression and its biological role within the mCRC immune microenvironment. METHODS: LAG3 expression was evaluated by immunohistochemistry in primary and/or metastatic tumors from a retrospective mCRC cohort. Associations between LAG3 expression, clinicopathological features, and overall survival were analyzed and validated using data from The Cancer Genome Atlas (TCGA) COADREAD cohort. Transcriptomic data from TCGA and single-cell RNA sequencing data from 23 Korean CRC samples were used to explore pathway enrichment and cell-cell interactions. RESULTS: A total of 144 mCRC patients were included. Primary tumors showed higher LAG3 expression than metastatic tumors, with right-sided and liver metastases exhibiting the highest level. Both univariate and multivariate analyses revealed that LAG3 expression was an independent prognostic biomarker of mCRC, validated in the TCGA COADREAD cohort. Transcriptomic analysis revealed significant correlations between LAG3 expression and angiogenesis, epithelial-mesenchymal transition, and TGF-β signaling pathways, which were linked to immunosuppressive microenvironment and poor prognosis. Cell-cell communication analysis showed CD8⁺ T cells interact with various cell subpopulations, with Galectin-9-TIM-3 signaling uniquely present in LAG3⁺CD8⁺ T cells. CONCLUSIONS: LAG3 expression is an independent prognostic biomarker of mCRC. The distinct Galectin-9-TIM-3 signaling in LAG3⁺CD8⁺ T cells may contribute to limited therapeutic efficacy of LAG3 blockade, suggesting potential combinational immunotherapy strategies.
Lin JR, Song YC, Chou YL
… +7 more, Chen YJ, Hsiao C, Li JP, Ho YJ, Liao WC, Yen HR, Liu CH
Cancer Immunol Immunother
· 2026 Mar · PMID 41770421
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Γδ T cells offer unique advantages in cancer immunotherapy because of their MHC-independent recognition of tumor antigens and innate cytotoxic potential. However, conventional ex vivo expansion protocols using zoledronic...Γδ T cells offer unique advantages in cancer immunotherapy because of their MHC-independent recognition of tumor antigens and innate cytotoxic potential. However, conventional ex vivo expansion protocols using zoledronic acid (Zol) and IL-2 often lead to terminal differentiation and diminished effector function. In this study, we performed a flow cytometry-based screen of an FDA-approved compound library to identify agents that enhance γδ T cell expansion while preserving their functional phenotypes. Dasatinib, a clinically used tyrosine kinase inhibitor, has emerged as a promising therapeutic candidate. Dasatinib-treated Vδ2 T cells (γδ2 T-Da) exhibited increased expansion, elevated expression of memory-associated markers (CD62L and CD127), reduced apoptosis, and higher production of TNF-α and IFN-γ. Transcriptomic analysis revealed the upregulation of genes related to T cell survival and self-renewal, including MYC, TCF7, and MIR155HG. Functionally, γδ2 T-Da cells demonstrated superior cytotoxicity against glioblastoma (GBM) and triple-negative breast cancer (TNBC) cells in vitro with sustained activity after prolonged culture. In orthotopic tumor models, γδ2 T-Da cells enhanced tumor control, reduced TNBC metastasis, and prolonged survival of GBM-bearing mice. These results suggest that dasatinib improves γδ T cell yield and function, providing a practical and translatable strategy for optimizing γδ T cell-based adoptive therapy, particularly for solid tumors.Trial registration: Trial number: CMUH111-REC3-185.
Kida S, Suga M, Yamaguchi Y
… +9 more, Ikeda S, Kogue Y, Kawamoto R, Shibata K, Tsutsumi K, Murakami H, Mizuta E, Mizutani Y, Hosen N
Cancer Immunol Immunother
· 2026 Mar · PMID 41770279
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CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML). However, CLL-1 AML cells are present in some patients, suggesting that the development of CAR T cells with high...CAR T cells targeting CLL-1 have shown antileukemia efficacy in patients with acute myeloid leukemia (AML). However, CLL-1 AML cells are present in some patients, suggesting that the development of CAR T cells with high sensitivity is necessary to eradicate all AML clones in these patients. Here, we identified CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody (mAb) that exhibited a significant anti-AML effect in vivo. We generated 13 new mAbs against CLL-1 and established CAR T cells from them. Of these, CAR T cells derived from mAb 2-23, which demonstrated greater affinity for CLL-1 than M26, the anti-CLL-1 mAb used in many previous studies, exhibited significant potential for cytokine production and cytotoxicity when co-cultured with AML cells. Treatment with 2-23 CAR T cells eradicated AML cells and significantly prolonged survival in AML xenograft models. Additionally, treatment with revumenib, a menin inhibitor, increased CLL-1 expression in AML cells harboring mixed-lineage leukemia (MLL) fusion genes or the NPM1 mutation, making them more susceptible to 2-23 CAR T cell-mediated cytotoxicity in vitro. These findings suggest that the clinical efficacy of CAR T cells derived from the novel, high-affinity anti-CLL-1 mAb 2-23 should be tested in patients with CLL-1-positive AML and also that combining 2-23 CAR T cells with revumenib may benefit some patients with CLL-1 AML.
Guan S, Wang C, Amann JM
… +3 more, Cho JH, Ma Q, Carbone DP
Cancer Immunol Immunother
· 2026 Feb · PMID 41762251
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BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, their low response rates and poor 5-year survivals indicate a need for improvement. One ke...BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, their low response rates and poor 5-year survivals indicate a need for improvement. One key factor in this resistance may be molecules that mediate immunosuppression within the tumor microenvironment (TME), such as adenosine. Combining therapies that mitigate the effects of adenosine with ICIs could potentially overcome these limitations. METHODS: We utilized the Lewis lung carcinoma (LLC) and CMT167 murine lung carcinoma models to investigate the combined use of the A2B receptor antagonist PBF1129 and anti-PD-1 ICI. The mechanisms underlying the efficacy of this combination therapy were explored using single-cell RNA sequencing (scRNA-seq). RESULTS: In both models, combination therapy improved tumor control. Our scRNA-seq analysis characterized alterations in malignant cells, macrophages, cancer-associated fibroblasts (CAFs), T cells, and endothelial cells in the tumor after treatment. Malignant cells treated with combination therapy exhibited reduced inflammatory, epithelial-to-mesenchymal transition (EMT) and angiogenic signatures. Malignant cells and M2-like macrophages showed high expression of TGFβ pathway genes, which were significantly reduced in the combination therapy group. We also observed decreased interactions between M2-like macrophages and CAFs as well as T cells, and dramatically increased Gzmb expression in M1-like macrophages with combination therapy. Combination therapy modulated TGFβ-mediated cellular crosstalk and extracellular matrix (ECM) remodeling. CONCLUSIONS: Our findings suggest that inhibition of adenosine activity by blocking the A2B receptor reduces TGFβ signaling and enhances the efficacy of ICI therapy in NSCLC.
Yamada H, Yamada R, Komohara Y
… +9 more, Pan C, Yoshii D, Yano H, Matsubara E, Shinchi Y, Tsukamoto H, Fujiwara Y, Ikeda K, Suzuki M
Cancer Immunol Immunother
· 2026 Feb · PMID 41762250
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OBJECTIVES: Inducible T cell costimulator (ICOS) is a CD28-family costimulatory receptor with bidirectional therapeutic effects on antitumor immunity, and HLA-mediated tumor recognition is essential for effective T cell...OBJECTIVES: Inducible T cell costimulator (ICOS) is a CD28-family costimulatory receptor with bidirectional therapeutic effects on antitumor immunity, and HLA-mediated tumor recognition is essential for effective T cell responses. However, their clinicopathological significance in lung adenocarcinoma (LUAD) is not fully understood. We investigated subset-specific pattern of ICOS expression and examined whether ICOS tumor-infiltrating lymphocyte (TIL) density and tumor HLA expression provide immune context and prognostic information in LUAD. MATERIALS AND METHODS: We examined 228 resected LUADs by immunohistochemistry. ICOS TIL density and HLA class I and HLA-DR status were compared with the densities of CD8, CD3CD8, and FOXP3 TILs and with postsurgical outcomes. Subset-specific ICOS expression was evaluated using multiplex pseudocolored immunohistochemistry in 10 representative cases selected from the ICOS TIL-high group and validated using a publicly available single-cell RNA-seq dataset. RESULTS: ICOS TIL density correlated with each T cell subset. Multiplex analysis showed the highest ICOS positivity among Tregs, followed by CD4 non-Tregs and CD8 TILs. Because CD4 non-Tregs were numerically predominant, ICOSCD4 non-Tregs constituted the largest ICOS fraction. Single-cell RNA-seq analysis corroborated these findings. ICOS TIL density was significantly higher in HLA-DR-strong tumors, and tumor HLA class I and HLA-DR were associated with longer recurrence-free survival. ICOS had no overall prognostic impact; however, among HLA-DR-strong tumors, ICOS-high patients tended toward longer cancer-specific survival. CONCLUSION: In LUAD, ICOS TIL density largely reflects ICOSCD4 non-Treg infiltration and is enriched in HLA-DR-strong tumors. Tumor HLA expression was associated with favorable prognosis, and ICOS may have context-dependent clinical significance that warrants further investigation.
Shukla GS, Pero SC, Sun Y
… +5 more, Mei L, Barrantes-Reynolds R, Fournier MR, Ackerman ME, Krag DN
Cancer Immunol Immunother
· 2026 Feb · PMID 41739229
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BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with advanced-stage disease frequently marked by treatment resistance and recurrence. Tumor heterogeneity, driven by the accumulati...BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with advanced-stage disease frequently marked by treatment resistance and recurrence. Tumor heterogeneity, driven by the accumulation of somatic mutations, undermines the efficacy of conventional therapies and limits the long-term success of targeted agents. There is an urgent need for new therapeutic strategies that can exploit, rather than be constrained by, this heterogeneity. METHODS: We developed a personalized immunotherapeutic pipeline in the syngeneic CT26 murine model of CRC. Briefly, whole exome sequencing identified mutated surface proteins (MSPs) unique to these cells. Of these MSPs, we selected 10 for the generation of MSP-specific polyclonal antibodies (pAbs). These pAbs were tested for specificity and peptide binding to peptides via ELISA, tumor tissue by immunofluorescence, and tumor cells by flow cytometry. Therapeutic efficacy was evaluated in vivo using CT26 tumor-bearing mice treated with the pAb cocktail alone or in combination with anti-PD-1 immune checkpoint blockade. To assess clinical relevance, we analyzed The Cancer Genome Atlas (TCGA) whole exome sequencing data from 100 human CRC patients for MSP prevalence and inter-patient variability. RESULTS: The 10-pAb oligoclonal antibody cocktail preparations exhibited additive, high-affinity, tumor-specific binding with minimal reactivity to healthy tissues. In vivo, this pAb cocktail significantly suppressed tumor growth and, when combined with PD-1 blockade, prolonged median survival to over 90 days in treated mice compared to less than 25 days in controls. Whole exome sequence data revealed that the majority of human CRC tumors harbored 10 or more MSPs, with minimal overlap between individuals, highlighting the feasibility and necessity of personalized antibody-based therapies. CONCLUSION: Our findings establish a proof-of-concept for individualized, mutation-guided antibody therapies, supporting further development of this approach to improve outcomes in patients with advanced CRC.
Yang Y, Wang S, Peng S
… +7 more, Li Y, Lei Y, Zheng W, Xu S, Huang S, Huang Y, Mao Y
Cancer Immunol Immunother
· 2026 Feb · PMID 41739217
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PURPOSE: To compare the efficacy of induction chemotherapy with or without PD-1 inhibitors followed by chemoradiotherapy (CCRT) among patients with human papillomavirus (HPV)-negative locally advanced head and neck squam...PURPOSE: To compare the efficacy of induction chemotherapy with or without PD-1 inhibitors followed by chemoradiotherapy (CCRT) among patients with human papillomavirus (HPV)-negative locally advanced head and neck squamous cell carcinoma (LA-HNSCC). MATERIALS AND METHODS: We retrospectively reviewed patients with HPV-negative LA-HNSCC who received induction chemotherapy with or without PD-1 inhibitors followed by CCRT between January 2018 and June 2023. Overall survival (OS), disease-free survival (DFS), and treatment-related adverse effects (TRAEs) were compared between the two groups overall and then in one-to-one propensity-score matched (PSM) cohorts. RESULTS: A total of 289 eligible patients were enrolled, with 120 patients received induction chemotherapy (the IC group), and 169 patients received induction chemotherapy combined with PD-1 inhibitors (the IC-IO group). Median follow-up was 39.3 months (range: 37.5-41.5 months). After PSM, objective response rate (ORR) was not significantly different in the IC-IO group versus the IC group (81.5% vs 74.1%, P = 0.19). The IC-IO group (vs. the IC group) had a superior 2-year OS (84.3% vs. 68.2%, P = 0.002) and DFS (74.1% vs. 56.9%, P = 0.005). G3/4 TRAEs between the two matched groups were comparable both during induction (11.1% vs 11.1%, P = 1.000) or CCRT (29.6% vs 38.9%, P = 0.152) phases. For the IC-IO group, no significant differences in OS (P = 0.68) or DFS (P = 0.29) were observed in the subset with versus without PD-1 inhibitors concurrently with CCRT. CONCLUSIONS: The addition of PD-1 inhibitors to IC significantly improves outcomes with tolerable TRAEs in patients with HPV-negative LA-HNSCC.
Ciccarese C, Occhipinti D, Arduini D
… +17 more, Di Leo D, Neri A, Roca L, Messina G, Troisi P, Pedone RR, Fucile MA, Belletto R, Sardaro V, Ligato C, Ajdhoni R, Caliciotti F, Sighinolfi C, Tagliaferri L, Rocco B, Tortora G, Iacovelli R
Cancer Immunol Immunother
· 2026 Feb · PMID 41739194
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BACKGROUND: Radical or partial nephrectomy followed by adjuvant pembrolizumab is the standard of care for high-risk localized renal cell carcinoma (RCC), yet around 40% of patients relapse within 5 years. We investigated...BACKGROUND: Radical or partial nephrectomy followed by adjuvant pembrolizumab is the standard of care for high-risk localized renal cell carcinoma (RCC), yet around 40% of patients relapse within 5 years. We investigated patterns of disease recurrence and the clinical management of RCC patients treated with adjuvant immunotherapy. MATERIALS AND METHODS: We collected patients with high-risk RCC who received adjuvant immunotherapy after radical surgery in our Institution. The primary endpoint was the rate and pattern of disease recurrence. Secondary endpoints were disease-free survival (DFS), overall survival (OS), post-progression survival (OS2) and treatments at recurrence. RESULTS: From March 2018 to September 2025, 70 patients were included, most received adjuvant pembrolizumab (71%), followed by nivolumab + ipilimumab (16%), and nivolumab monotherapy (13%). 15 patients (21%) experienced recurrence, including 7 (10%) who relapsed on adjuvant treatment. Oligometastatic disease was observed in 10 cases (67%), mainly involving lung (60%), lymph nodes (33%) and renal bed (13%). At recurrence, 9 patients (60%) started first-line therapy, while 5 patients (33%) received loco-regional treatments. After a median follow-up of 30.2 months, 30-month DFS and OS rates were 74% and 94%, respectively, in the overall population. Among patients who progressed, the 24-month OS2 rate was 100% after local therapy alone and 86% with systemic therapy. CONCLUSIONS: High-risk RCC patients treated with adjuvant immunotherapy remain at considerable risk of relapse, frequently with oligometastatic disease. Excellent post-progression outcomes after loco-regional treatment support a multidisciplinary, metastasis-directed approach to recurrence after adjuvant immunotherapy.
Yanagisawa T, Mori K, Kawada T
… +19 more, Katayama S, Tsujino T, Maenosono R, Toyoda S, Nukaya T, Morinaka H, Tamura K, Fukuokaya W, Urabe F, Murakami M, Bekku K, Takahara K, Fujita K, Azuma H, Araki M, Inamoto T, Komura K, Kimura T, JK-FOOT study group
Cancer Immunol Immunother
· 2026 Feb · PMID 41739193
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PURPOSE: Immune checkpoint inhibitor (ICI)-based combination therapy is a standard first-line treatment for metastatic renal cell carcinoma (mRCC), with combinations such as nivolumab plus cabozantinib (Nivo + Cabo) and...PURPOSE: Immune checkpoint inhibitor (ICI)-based combination therapy is a standard first-line treatment for metastatic renal cell carcinoma (mRCC), with combinations such as nivolumab plus cabozantinib (Nivo + Cabo) and pembrolizumab plus lenvatinib (Pem + Len) demonstrating favorable oncologic outcomes. However, no direct comparisons between these two regimens have been conducted. This study aimed to compare the safety and oncologic outcomes of Nivo + Cabo and Pem + Len in patients with mRCC. METHODS: This retrospective study included 185 patients with mRCC treated with Nivo + Cabo (n = 81) or Pem + Len (n = 104) between January 2018 and June 2025 across multiple institutions. The primary outcome was a comparison of treatment-related adverse events (TrAEs). Oncologic outcomes, including objective response rate (ORR), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were compared using one-to-one propensity score matching. RESULTS: Any-grade TrAEs occurred in 90% of patients in the Nivo + Cabo group and 92% in the Pem + Len group (p = 0.6). Severe TrAEs (grade ≥ 3) were more frequent in the Pem + Len group (44%) than in the Nivo + Cabo group (30%, p = 0.048). Tyrosine kinase inhibitor dose reduction and treatment discontinuation rates were similar between groups. In the matched cohort (Nivo + Cabo: n = 74; Pem + Len: n = 74), ORRs were comparable (66% vs. 71%, p = 0.6). With a median follow-up of 17 months, no significant differences were observed in PFS (p = 0.4), CSS (p = 0.9), or OS (p = 0.5). CONCLUSIONS: Nivo + Cabo and Pem + Len demonstrated similar oncologic efficacy as first-line treatments for mRCC. However, Pem + Len was associated with more severe TrAEs. Careful toxicity management and shared decision-making are essential when selecting ICI-based combinations.
Huang CH, Chen JY, Chang HY
… +9 more, Hong WZ, Jiang YW, Lee CY, Wu CH, Lin YS, Tsai YY, Kao WL, Chao KSC, Huang KC
Cancer Immunol Immunother
· 2026 Feb · PMID 41739190
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Therapeutic cancer vaccines, which induce anti-tumor immunity by targeting specific antigens, constitute a promising approach to cancer therapy. Our previous work developed a novel engineered adenovirus-associated virus...Therapeutic cancer vaccines, which induce anti-tumor immunity by targeting specific antigens, constitute a promising approach to cancer therapy. Our previous work developed a novel engineered adenovirus-associated virus 2 (AAV2)-based tumor-specific (neoantigen) cancer vaccine to boost antitumor immunity in combination with radiotherapy, resulting in tumor regression and less distant metastasis. However, the therapeutic efficacy of constitutive vector-based vaccination may be limited by poor immunogenicity, pre-existing vector-specific immunity, and vaccine-induced vector-specific immunity. Here, we examined the combinational therapeutic efficacy of AAV-based cancer vaccine, local radiotherapy, and immune checkpoint blockade (ICB) in different poorly immunogenic cancer animal models. We found that administration with AAV-based neoantigen vaccine significantly increased the response to radiotherapy and ICB, and decreased the risk of distant metastasis. Furthermore, we evaluated a heterologous prime-boost immunization strategy using two optimized AAV serotype vaccines to amplify tumor-specific immunity to neoantigens. These optimized AAV2/AAV6 neoantigen vaccine displayed strong immunogenicity with potent induction of CD8 T cells. As combined with local radiotherapy, the prime-boost vaccine-induced superior tumor clearance and survival compared with other groups. Remarkably, optimized AAV2/AAV6 vaccination promoted CD8 T-cell infiltration in the tumors and elicited the enrichment of T-cell clones. Furthermore, exhausted T-cell marker expression was significantly decreased in the tumor-infiltrating CD8 T cells. Taken together, these results highlight the synergistic potency of engineered AAV2/AAV6 vaccines combined with local radiotherapy for poorly immunogenic cancers.
Nagare M, Sahoo M, Sengar M
… +19 more, Punatar S, Khattry N, Gokarn A, Bagal B, Jain H, Mirgh S, Epari S, Shet T, Pradhan T, Shirsat S, Barkume M, Mathen C, Gera P, Verma RK, Saldanha E, Chandrani P, Gawde J, Chiplunkar S, Kode J
Cancer Immunol Immunother
· 2026 Feb · PMID 41729306
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BACKGROUND: Bone marrow-resident mesenchymal stem cells (BM-MSC) often play a role in acute myeloid leukemia (AML) progression and drug resistance by exerting immunomodulatory effects on cellular as well as soluble milie...BACKGROUND: Bone marrow-resident mesenchymal stem cells (BM-MSC) often play a role in acute myeloid leukemia (AML) progression and drug resistance by exerting immunomodulatory effects on cellular as well as soluble milieu. The current study aimed to understand the dynamic interplay between AML-BM-MSC and their soluble factors in determining the fate of AML blasts within the microenvironment. METHODS: AML-BM-MSC were cultured and characterized for expression of phenotyping markers, multilineage differentiation potential, and gene expression analysis by microarray. To understand cross talk, AML-BM-MSC were co-cultured with the AML cell line OCI-AML2 and assessed for changes in cell cycle phases, mitochondrial activity, and cytarabine-induced cell death. Differential regulation of AML blast fate was evaluated by conducting co-culture experiments with cell-free-conditioned media (PD-MSC-CM) and in the presence of cell-cell contact of AML-BM-MSC. Further, PD-MSC-CM was assessed in vivo for tumor reduction potential using a leukemia xenograft model. RESULTS: Besides standard features, AML-BM-MSC exhibited increased vesicles, MSC bodies (exosomes), and mitochondria. Altered AML-BM-MSC demonstrated upregulation of inflammasome pathway markers in microarray, which was further validated by ELISA and quantitative real-time polymerase chain reaction. Co-culture experiments on AML-BM-MSC revealed protective effects on AML blasts in the presence of cytarabine. In contrast, PD-MSC-CM significantly inhibited AML cell growth alone and synergistically with cytarabine. Further, PD-MSC-CM significantly reduced tumor growth in the leukemia mouse model, and this effect was mediated by regulation of the NLRP3 inflammasome pathway. CONCLUSION: Summarizing, the leukemic blasts and AML-MSC in the BM microenvironment interact differentially in cell-cell contact compared to only soluble factors. Further, our study has provided innovative leads that PD-MSC-CM effectively abrogates leukemia tumor growth, enhances chemosensitivity and can be developed further as an immunomodulatory novel "off-the-shelf" therapeutic agent for leukemia.
Ma J, Xu F, Wang M
… +8 more, Zhang S, Sang J, Chen H, Wen F, Ge R, Xie Q, Wei Z, Ye X
Cancer Immunol Immunother
· 2026 Feb · PMID 41711960
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OBJECTIVE: Microwave ablation (MWA) has shown favorable safety and efficacy in patients with non-small cell lung cancer (NSCLC). However, local recurrence remains a major concern that compromises long-term survival. Dysf...OBJECTIVE: Microwave ablation (MWA) has shown favorable safety and efficacy in patients with non-small cell lung cancer (NSCLC). However, local recurrence remains a major concern that compromises long-term survival. Dysfunction of dendritic cells (DCs) constitutes a key immunosuppressive factor that limits effective T cell-mediated antitumor responses. To overcome this limitation, we evaluated the therapeutic potential of combining MWA with DC-based immunotherapy. METHODS: A Lewis lung carcinoma (LLC) rechallenge mouse model was established to assess the efficacy of the combination of MWA and DC therapy in preventing post-ablation tumor recurrence. The immune landscape in tumors and tumor-draining lymph nodes (TdLNs) was analyzed by flow cytometry. RESULTS: The combination of MWA and DC therapy markedly suppressed tumor recurrence and promoted potent antitumor immunity, as evidenced by an increased proportion and functional activation of CD8⁺ T cells in both recurrent tumors and TdLNs. In addition, the combination treatment substantially increased the frequency and immunostimulatory capacity of migratory type 1 conventional dendritic cells (Mig cDC1s) within TdLNs. These results indicate that cDC1s are crucial mediators of the enhanced antitumor response induced by MWA combined with DC therapy. CONCLUSION: Our findings highlight a synergistic antitumor mechanism of MWA and DC-based therapy through cDC1 activation and CD8⁺ T cell enhancement, providing a promising strategy to reduce tumor recurrence after MWA.
Hamada K, Hamanishi J, Ueda A
… +15 more, Takamatsu S, Yoshihara K, Nagasawa T, Seki T, Kikuchi A, Fujimoto E, Taki M, Yamanoi K, Murakami R, Kumada K, Oda K, Shimada M, Okamoto A, Mandai M, Matsumura N
Cancer Immunol Immunother
· 2026 Feb · PMID 41697393
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Transcriptomic classification methods have been proposed for ovarian clear cell carcinoma. However, their clinical significance and association with pathologically evaluated tumor-infiltrating lymphocytes (TILs) remain u...Transcriptomic classification methods have been proposed for ovarian clear cell carcinoma. However, their clinical significance and association with pathologically evaluated tumor-infiltrating lymphocytes (TILs) remain unclear. We established two large transcriptomic datasets and analyzed RNA-sequencing data from 189 (JGOG3025-TR1 cohort) and 38 (Kyoto cohort) ovarian clear cell carcinomas. Representative histopathological slides were also digitized (102 and 38, respectively). Cell types were classified by two state-of-the-art artificial-intelligence models, and TILs were quantified. The transcriptomically defined immune subtype was associated with significantly poor prognosis (hazard ratio, 2.54; 95% CI, 1.42-4.54; p = 0.002 for OS). However, this group also contained significantly higher proportion of advanced-stage cases (p = 0.003), and multivariate analyses showed no independent prognostic effect (hazard ratio, 1.32; 95% CI, 0.68-2.58; p = 0.42 for OS). In contrast, the pathologically defined inflamed group demonstrated a trend toward improved survival, and the inflamed phenotype emerged as a statistically significant favorable prognostic factor for both OS and PFS in multivariate analyses (hazard ratio, 0.32; 95% CI, 0.13-0.78; p = 0.013 for OS. hazard ratio, 0.32; 95% CI, 0.15-0.67; p = 0.0026 for PFS). These findings indicate a discordance between transcriptome- and pathology-based immune classifications and suggest greater prognostic relevance of pathology-derived immune status.
Roviello G, Gambale E, De Gennaro Aquino I
… +29 more, Maruzzo M, Messina C, Vascotto IA, Rossi V, Bimbatti D, Erbetta E, Messina M, Mennitto A, Rebuzzi SE, Nasso C, Mercinelli C, Catalano M, Maiorano BA, Fanelli M, Sorarù M, Scolari F, Mela MM, Galli L, Salfi A, Rizzo M, Puglisi S, Orlando V, Fornarini G, Rametta A, Giannatempo P, Cerbone L, Doni L, Pillozzi S, Antonuzzo L
Cancer Immunol Immunother
· 2026 Feb · PMID 41689638
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BACKGROUND: In advanced urothelial carcinoma (UC), the prognostic impact of metastatic site and burden during avelumab maintenance therapy remains poorly defined. METHODS: We performed a sub-analysis of the Italian multi...BACKGROUND: In advanced urothelial carcinoma (UC), the prognostic impact of metastatic site and burden during avelumab maintenance therapy remains poorly defined. METHODS: We performed a sub-analysis of the Italian multicenter retrospective-prospective observational study Meet-URO 25, including patients with advanced UC who received avelumab maintenance after disease control with first-line platinum-based chemotherapy. We assessed the association between metastatic site and number of metastatic sites at the start of avelumab and clinical outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 243 patients were included. Lymph nodes (79.0%), lungs (32.1%), and bones (27.2%) were the most common metastatic sites. The median number of metastatic sites at the start of avelumab maintenance was 1. ORR and disease control rate (DCR) were higher in patients with nodal-only disease (ORR 28.9%, DCR 69.4%) and significantly lower in those with bone metastases (ORR 9.8%, DCR 50.8%). Median PFS and OS were 7.4 and 24.1 months, respectively, in the overall cohort. Bone metastases were associated with markedly shorter PFS (3.7 vs. 8.2 months; HR 1.92, p < 0.001) and OS (11.3 vs. 27.6 months; HR 2.44, p < 0.001), especially when present as a single metastatic site. Increasing number of metastatic sites was also associated with poorer outcomes (OS: 35.5 months with one site vs. 11.9 months with ≥ 3 sites; p < 0.001). CONCLUSIONS: In this real-world cohort, both metastatic site and burden strongly influenced response and survival of avelumab. Bone metastases were independently associated with poor prognosis, while nodal-only disease identified a favorable subgroup. These findings support risk-based treatment stratification in the maintenance setting.
Bhojnagarwala PS, Bordoloi D, Jose J
… +4 more, Perales-Puchalt A, Yan J, Sardesai NY, Weiner DB
Cancer Immunol Immunother
· 2026 Feb · PMID 41689634
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T cell lymphomas constitute approximately 10% of all non-Hodgkin lymphomas and are associated with poor prognosis. Patients experiencing early relapse post-treatment exhibit a 5-year overall survival rate of 11%, undersc...T cell lymphomas constitute approximately 10% of all non-Hodgkin lymphomas and are associated with poor prognosis. Patients experiencing early relapse post-treatment exhibit a 5-year overall survival rate of 11%, underscoring the need for improved therapeutic strategies. The clonality of T cell cancers makes the T cell receptor (TCR) an appealing target for immunotherapy. Here, we developed and evaluated a synDNA vaccine against the TCR⍺, β, and γ chains (TCRfullvax) of the EL4 murine T cell lymphoma model. Immunogenicity studies revealed induction of robust T cell responses against all three TCR chains, with identification of immunodominant epitopes for each chain. Notably, we observed no significant differences in the number of live T cells between TCRfullvax-vaccinated group and control groups, indicating the vaccine's ability to selectively break tolerance against vaccinated TCR without broadly depleting T cells. In a minimal residual disease model, TCRfullvax delayed EL4 tumor progression. Tumors from TCRfullvax-treated mice revealed downregulation of TCR expression, suggesting a potential immune escape mechanism. Neoantigens, derived from somatic mutations within tumor genome, present another promising target for anticancer vaccine development, accordingly we developed a second vaccine targeting 15 neoantigens identified through sequencing of EL4 cells (EL4neovax). EL4neovax elicited strong immune responses against 5/15 encoded neoantigens and controlled EL4 tumors. Co-administration of TCRfullvax and EL4neovax demonstrated superior tumor control compared to either vaccine design alone, further supporting that neoantigen targeting can partially mitigate TCR loss. These findings highlight the potential of combining TCR-targeted and neoantigen-based immunotherapies for the treatment of T cell lymphomas. Further investigation of this dual-vaccine approach is warranted to optimize the therapeutic efficacy for this difficult disease.
Zhou Q, Wang Z, Cao Y
… +6 more, Zheng Z, Li W, Fu Z, Luo W, Gao WQ, Ma B
Cancer Immunol Immunother
· 2026 Feb · PMID 41677949
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Pattern recognition receptors (PRRs) are crucial modulators of the tumor immune microenvironment (TIME); yet, their comparative efficacy remains poorly characterized. Platelet factor 4 (PF4/CXCL4) exerts paradoxical effe...Pattern recognition receptors (PRRs) are crucial modulators of the tumor immune microenvironment (TIME); yet, their comparative efficacy remains poorly characterized. Platelet factor 4 (PF4/CXCL4) exerts paradoxical effects in cancer, and its regulation by PRR signaling is unclear. Here, we systematically screened PRR agonists in murine tumor models and identified TLR8 agonists as the most potent inducers of a pro-immunogenic TIME, superior to agonists targeting TLR3/7/9 or NOD1/2. TLR8 activation drove CD45 leukocyte infiltration, potentiated conventional dendritic cell (cDC) and macrophage phagocytosis and migration, amplified recruitment of CD8 and conventional CD4 (cCD4) T cells, lowered Treg proportions, elicited pro-inflammatory and tumoricidal phenotypes in innate immune cells and CD8 T cells. Notably, TLR8 agonism suppressed tumor growth in both immunocompetent and T cell-deficient mice, indicating the involvement of both innate and adaptive immunity. Mechanistically, TLR8 agonists upregulated PF4 expression in macrophages, cDC2, and CD8 T cells via the NF-κB pathway. PF4 in turn recruited cCD4 T cells via CXCR3, and its local overexpression mimicked the antitumor effect of TLR8 activation. Beyond PF4, TLR8 signaling mediated PF4-independent effects, including Treg suppression via IFN-γ and enhanced macrophage phagocytosis. Combination of a TLR8 agonist with anti-PD-1 therapy markedly and synergistically improved survival of tumor-bearing mice. Thus, TLR8 agonists optimally remodel the TIME through PF4-dependent T cell recruitment and PF4-independent ancillary mechanisms. Our finding that the antitumor activity of locally induced PF4 contrasts with its reported protumor effects when expressed systemically clarifies the context-dependent duality of PF4 in cancer. These results position TLR8 agonists as promising candidates for combination immunotherapy.
Hidalgo L, Garcia-Rodriguez P, Cubillo I
… +3 more, Zubizarreta M, Perez-Martinez A, García-Castro J
Cancer Immunol Immunother
· 2026 Feb · PMID 41677938
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Cancer is the leading cause of death among children and adolescents in high-income countries. Among solid tumors, osteosarcoma (OS) is the most prevalent primary bone cancer in the pediatric population. For patients who...Cancer is the leading cause of death among children and adolescents in high-income countries. Among solid tumors, osteosarcoma (OS) is the most prevalent primary bone cancer in the pediatric population. For patients who relapse or develop metastases, the survival rate remains at only 30%, with scarce improvement over the past 30 years. Immunotherapy, including chimeric antigen receptor (CAR) T cells, represents a promising approach to treating OS. We observed that despite robust in vitro cytotoxicity of NKG2D-CAR T at low effector-to-target ratios, NKG2D-CAR T cells failed to control tumor growth in our xenograft OS models, highlighting the suppressive tumor microenvironment (TME). In this regard, the hypoxic TME has been widely considered a barrier to effective immunotherapies. Here, we examined the impact of hypoxia on NKG2D-CAR T function in OS in vitro models. We confirmed HIF-1α is highly expressed in our OS models, indicating the potential of hypoxia as a CAR T disruptor. However, hypoxia was not responsible for lowering NKG2D ligands expression for CAR recognition, nor did it impact the expression of major activating or inhibitory immune checkpoints. Crucially, functional assays demonstrated that NKG2D-CAR T cell phenotype, activity, and cytokine secretion remained unaffected and its activity against three-dimensional OS-spheroids was preserved under in vitro hypoxic conditions. Although these findings challenge the idea that hypoxia alone compromises in vitro NKG2D-CAR T efficacy in OS, further studies are needed on how hypoxia interacts with multiple factors of the TME that could modulate CAR T cell behavior.
Cancer Immunol Immunother
· 2026 Feb · PMID 41677907
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BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB). While early phase studies have demonstrated activity of dual ICB with anti-PD-1 plus anti-CTLA-4 agents in bo...BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB). While early phase studies have demonstrated activity of dual ICB with anti-PD-1 plus anti-CTLA-4 agents in both the first- and second-line settings, the role of combination therapy as a first-line approach remains controversial. METHODS: We conducted a systematic review and meta-analysis to summarize the current evidence of first-line ICB therapy in MCC and to compare the pooled objective response rate (ORR) between combination ICB and monotherapy. Pooled ORRs were estimated using fixed-effects meta-analyses, and these results were statistically compared between combination ICB and monotherapy. In addition to the meta-analysis and as real-world validation, we performed a retrospective chart review of MCC patients treated with first-line combination ICB at a single referral center. RESULTS: In the meta-analysis, the pooled ORR of ipilimumab plus nivolumab was significantly higher than that of either anti-PD(L)1 monotherapy when considering all anti-PD-1 and anti-PD-L1 agents (81.0% vs. 49.6%, p = 0.0001) as well as monotherapy when restricted to anti-PD-1 agents (81.0% vs. 57.0%, p = 0.0043). Concordant with pooled trial findings, we identified eight patients treated off protocol with first-line combination ICB at our institution, with seven (87.5%) achieving objective response. DISCUSSION: Based on meta-analysis of clinical trial data, first-line treatment of advanced Merkel cell carcinoma with ipilimumab plus nivolumab results in a higher objective response rate compared to monotherapy. The clinical decision to select combination therapy over monotherapy must weigh this response rate benefit with the unknown survival benefit and higher toxicity.
Rincón-López S, Atencio-Matos J, Pereda-Sainz O
… +13 more, Larreina-Pérez J, Campeny-Najara A, Esteban-Figuerola A, Hernandez-Perez M, Garrastachu-Zumaran P, Velasco-Ruiz M, García-Bosque I, Rodriguez-Lefler C, Ruiz de Gaona E, Feliu J, Cabello J, Martín-Carnicero A, García-Muñoz R
Cancer Immunol Immunother
· 2026 Feb · PMID 41677892
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PURPOSE: Diffuse large B cell lymphoma (DLBCL) is characterized by high relapse rates and immunobiological complexity. The therapeutic efficacy of CD20-targeting monoclonal antibodies depends largely on antibody-dependen...PURPOSE: Diffuse large B cell lymphoma (DLBCL) is characterized by high relapse rates and immunobiological complexity. The therapeutic efficacy of CD20-targeting monoclonal antibodies depends largely on antibody-dependent cellular cytotoxicity (ADCC), mediated by natural killer (NK) cells. METHODS: We evaluated the percentage of bone marrow NK cells in 47 newly diagnosed DLBCL patients by flow cytometry prior to first-line chemoimmunotherapy. ADCC potential was assessed using immunological parameters. RESULTS: Patients with ≥ 14% bone marrow NK cells had significantly better event-free survival (EFS), with median EFS nearly doubled compared with those below this threshold (HR = 0.24, p < 0.05). Logistic regression predicted a 77% probability of remaining relapse-free at NK percentages > 14%. In multivariable Cox regression, bone marrow NK percentage remained independently predictive of EFS after adjustment for International Prognostic Index (IPI), age, and treatment regimen. Although overall survival did not differ significantly, higher NK levels were associated with improved clinical response. CONCLUSION: Patients with higher NK cell percentages may better tolerate chemotherapy-induced depletion, thereby preserving or restoring their effector pool more efficiently. Elevated bone marrow NK cell percentages predict favorable outcomes in DLBCL and support their potential role as translational biomarkers. Incorporating NK cell monitoring into clinical protocols could improve risk stratification and guide immunotherapeutic strategies for personalized patient management.