Journal for Immunotherapy of Cancer最新文献

{"title":"Novel anti-CD73-IL-2v bispecific fusion protein augments antitumor immunity by alleviating immunosuppressive adenosine pathways in CD8⁺ T cells.","authors":"Kayoung Shin, Min Park, Seoho Kim, Haejong Lee, Yuseong Lee, Jongil Kim, Suyoun Park, Jisoo Kim, Kyungwha Lee, Chong Woo Park, Ji-Hyun Kim, Eun-Jin Lee, Hyuckjun Mok, Sung-Man Oh, Sanghee Lee, Young Min Oh, Wonjae Lee, Yaein Amy Shim, Young-Gyu Cho, Junsik Park, Jung-Yun Lee, Young Jun Koh, Kook Hwan Kim, Myoung Ho Jang","doi":"10.1136/jitc-2023-008594","DOIUrl":"https://doi.org/10.1136/jitc-2023-008594","url":null,"abstract":"<p><strong>Background: </strong>Adenosine accumulated in the tumor microenvironment functions as an immune-modulating factor, exerting immunosuppressive actions via adenosine A2A/A2B receptor (A2AR/A2BR) in various immune cell types. CD73, a key enzymatic regulator responsible for adenosine production, is frequently overexpressed in diverse cancers, and its overexpression is associated with reduced responsiveness to conventional anti-cancer drug treatments such as chemotherapy, radiation therapy, targeted therapy, or immunotherapy. Despite numerous therapeutic applications of IL-2 in cancer immunotherapy, the relationship between the CD73-adenosine axis and IL-2-based immunotherapy remains largely unexplored.</p><p><strong>Methods: </strong>To evaluate the effect of CD73 blockade on IL-2 signaling of CD8⁺ T cells, we screened novel CD73 antibodies using human single-chain variable fragment phage library and immunized Alpaca phage library. To optimize targeting to CD73-expressing cells and reinvigorate the antitumor effect of IL-2 in adenosine-rich microenvironment, we engineered a novel bifunctional GI-αCD73/IL-2v fusion protein. Functionality of GI-αCD73/IL-2v fusion protein was assessed in the in vitro cell-based assays and the in vivo tumor-bearing mouse model or cynomolgus monkey.</p><p><strong>Results: </strong>IL-2-induced increase in proliferation of CD8⁺ T cells was not observed under adenosine-rich microenvironment. We demonstrated that the functional impairment of IL-2 signaling in CD8⁺ T cells in these conditions can be reversed by our anti-CD73 antibody (GI-αCD73). Furthermore, GI-αCD73/IL-2v fusion protein significantly restored the impaired proliferation of CD8⁺ T cells and consequently enhanced tumor cell killing under adenosine-mediated immunosuppression, surpassing the combined treatment of GI-αCD73 and Fc-IL-2v. These synergistic effects were attributed to the enhanced delivery of the IL-2v component of GI-αCD73/IL-2v to IL-2Rβγ on CD73-expressing CD8⁺ T cells through a cis-binding mechanism. GI-αCD73/IL-2v elicited a potent antitumor effect in both the human CD73 knock-in (hCD73 KI) mouse model and the humanized mouse model. In non-human primates, GI-αCD73/IL-2v exhibited excellent tolerability while inducing robust and durable expansions of cytotoxic lymphocytes.</p><p><strong>Conclusions: </strong>GI-αCD73/IL-2v bispecific protein is a novel and potent immunocytokine with significant antitumor immunity through cis-binding on CD8⁺ T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fc-mediated immune stimulating, pro-inflammatory and antitumor effects of anti-HER2 IgE against HER2-expressing and trastuzumab-resistant tumors.","authors":"Melanie Grandits, Lais C G F Palhares, Gabriel Osborn, Jitesh Chauhan, Katie Stoker, Heng Sheng Sow, Rebecca Adams, Alex J McCraw, Alicia Chenoweth, Sofia Vlasova, Jacobo López-Abente, Kristina M Ilieva, James Birtley, Sophia Tsoka, Elizabeth Hardaker, Kevin FitzGerald, Sophia N Karagiannis, Heather J Bax","doi":"10.1136/jitc-2024-010945","DOIUrl":"https://doi.org/10.1136/jitc-2024-010945","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Anti-human epidermal growth factor receptor 2 (HER2) IgG1-based antibody therapies significantly improve cancer prognosis, yet intrinsic or acquired resistance to fragment antigen-binding (Fab)-mediated direct effects commonly occurs. Most resistant tumors retain antigen expression and therefore remain potentially targetable with anti-HER2 therapies that promote immune-mediated responses. Tumor-antigen-specific IgE class antibodies can mediate powerful immune cell-mediated effects against different cancers and have been shown to activate IgE Fc receptor-expressing monocytes. We previously reported the engineering of a trastuzumab-equivalent anti-HER2 IgE antibody and showed early evidence of Fc-mediated cancer cell-targeting effects. In the present study, we evaluated the anti-tumoral functions of two anti-HER2 IgEs, trastuzumab and pertuzumab IgE.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In vitro functionality of the two anti-HER2 antibodies was assessed by HER2 phosphorylation and ligand-independent viability assays, as well as basophil (RBL-SX38) degranulation, antibody-dependent cellular cytotoxicity/antibody-dependent cellular phagocytosis(ADCC/ADCP) assays and primary monocyte stimulation assays. The potential to trigger a hypersensitivity type I reaction was investigated using the basophil activation test (BAT). anti-tumoral efficacy was assessed in two humanized HER2+, trastuzumab-resistant models in vivo. Changes in the tumor microenvironment were assessed by flow cytometry or bulk RNA sequencing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We demonstrate the anti-tumoral and immunostimulatory functions of two anti-HER2 IgEs derived from variable region sequences of the clinically available trastuzumab and pertuzumab IgG1 antibodies. IgE engagement of monocytes via the Fc region induced tumor cell cytotoxicity and a pro-inflammatory shift with upregulation of immune-stimulatory CD40, CD80 and CD86, and downregulation of scavenger CD163, cell surface molecules. This was accompanied by enhanced pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β cytokine production. The absence of basophil activation by anti-HER2 IgEs ex vivo in whole blood points to potentially safe administration in humans. In two trastuzumab-resistant HER2+ tumor xenograft models in immunodeficient mice reconstituted with human immune cells, the trastuzumab-equivalent anti-HER2 IgE restricted tumor growth. Treatment was associated with enriched classical (CD14&lt;sup&gt;+&lt;/sup&gt;CD16&lt;sup&gt;-&lt;/sup&gt;) monocyte and lower alternatively-activated (CD163&lt;sup&gt;+&lt;/sup&gt;CD206&lt;sup&gt;+&lt;/sup&gt;) macrophage infiltration, and higher densities of activated CD4&lt;sup&gt;+&lt;/sup&gt; (CD127&lt;sup&gt;lo&lt;/sup&gt;CD25&lt;sup&gt;hi&lt;/sup&gt;) T cells and favorable effector T cell(Teff) to regulatory T cell (Treg) ratios in tumors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Collectively, anti-HER2 IgE maintains Fab-mediated antitumor activity, induces Fc-mediated effects against HER2-expressing tumor cells, and","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Society for Immunotherapy of Cancer (SITC) consensus statement on essential biomarkers for immunotherapy clinical protocols.","authors":"Tricia R Cottrell, Michael T Lotze, Alaa Ali, Carlo B Bifulco, Christian M Capitini, Laura Q M Chow, Anthony R Cillo, Deborah Collyar, Leslie Cope, Julie Stein Deutsch, Genia Dubrovsky, Sacha Gnjatic, Denise Goh, Susan Halabi, Gary Kohanbash, Holden T Maecker, Saman Maleki Vareki, Sarah Mullin, Barbara Seliger, Janis Taube, Wim Vos, Joe Yeong, Kristin G Anderson, Tullia C Bruno, Codruta Chiuzan, Ivan Diaz-Padilla, Elizabeth Garrett-Mayer, Isabella C Glitza Oliva, Paola Grandi, Elizabeth G Hill, Brian P Hobbs, Yana G Najjar, Phyllis Pettit Nassi, Virgil H Simons, Sumit K Subudhi, Ryan J Sullivan, Chris H Takimoto","doi":"10.1136/jitc-2024-010928","DOIUrl":"10.1136/jitc-2024-010928","url":null,"abstract":"<p><p>Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells. The drive to develop increasingly effective immunotherapy regimens is tempered by the risk of immune-related adverse events. Evidence-based biomarkers that measure the potential for therapeutic response and/or toxicity are critical to guide optimal patient care and contextualize the results of immunotherapy clinical trials. Responding to the lack of guidance on biomarker testing in early-phase immunotherapy clinical trials, we propose a definition and listing of essential biomarkers recommended for inclusion in all such protocols. These recommendations are based on consensus provided by the Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty with input from the SITC Pathology and Biomarker Committees and the Journal for ImmunoTherapy of Cancer readership. A consensus-based selection of essential biomarkers was conducted using a Delphi survey of SCION faculty. Regular updates to these recommendations are planned. The inaugural list of essential biomarkers includes complete blood count with differential to generate a neutrophil-to-lymphocyte ratio or systemic immune-inflammation index, serum lactate dehydrogenase and albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, and tumor mutational burden. Inclusion of these biomarkers across early-phase immunotherapy clinical trials will capture variation among trials, provide deeper insight into the novel and established therapies, and support improved patient selection and stratification for later-phase clinical trials.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunosuppressive microenvironment of liver restrains chemotherapeutic efficacy in triple-negative breast cancer.","authors":"Mingduo Liu, Mengjia Qian, Wen Sun, Xiaowei Sun, Yue Sun, Muxin Yu, Xinyu Tang, Xinrui Mao, Chang Sun, Qi Qi, Weiya Zhang, Peiwen Ling, Zheng Pang, Wei Li, Hong Pan, Shui Wang, Wenbin Zhou","doi":"10.1136/jitc-2024-010871","DOIUrl":"https://doi.org/10.1136/jitc-2024-010871","url":null,"abstract":"<p><strong>Background: </strong>Patients with liver metastases of triple-negative breast cancer (TNBC) show poor prognosis compared with other metastases. Chemotherapy is the primary treatment for advanced TNBC. Tumor cell diversity and the tumor microenvironment could affect therapeutic effect. However, whether liver metastases of TNBC exhibit differential chemotherapy efficacy compared with the primary tumors remains inadequately understood. The specific mechanisms that modulate chemotherapy efficacy in liver metastases need further investigation.</p><p><strong>Methods: </strong>Single-cell RNA sequencing data from public databases were leveraged to contrast the immune profiles of liver metastases and primary tumors in TNBC. Murine models bearing liver tumors or primary tumors of TNBC were used to evaluate chemotherapy efficacy. Techniques such as immunohistochemistry, wound healing assays, and colony formation assays were employed to account for tumor heterogeneity. Intratumoral T lymphocytes and macrophages were quantified and characterized using RNA sequencing, immunohistochemistry, and flow cytometry. Antibody-mediated depletion of CD8+T cells or macrophages in mice substantiated their impact on chemotherapy responses.</p><p><strong>Results: </strong>Single-cell RNA sequencing data showed the immune microenvironments of liver metastases and primary tumors exhibited significant differences, which may critically influence chemotherapy outcomes. Mouse models confirmed that chemotherapy was less effective against liver tumors compared with subcutaneous tumors. After excluding the influence of tumor cell heterogeneity, the weaker responsiveness in liver tumors was mediated by the impeded infiltration of CD8+T cells, attributed to the decreased activation of macrophages. Augmenting macrophage activation can improve the chemotherapeutic efficacy in liver tumors. Moreover, chemotherapy drove the immune microenvironment towards increased suppression through distinct mechanisms, with neutrophil extracellular traps (NETs) accumulating in liver tumors and impaired functionality of macrophages at the primary site. The combination of NET inhibitors or macrophage activators with chemotherapy enhanced treatment effectiveness.</p><p><strong>Conclusions: </strong>These findings disclose the compromised chemotherapeutic efficacy in liver tumors of TNBC and elucidate the underlying immune-related mechanisms within the tumor microenvironment. Targeting the specific underpinnings of immune suppression at different tumor sites with selective drugs could optimize chemotherapeutic efficacy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on 'Pembrolizumab hybrid dosing is non-inferior to flat dosing in advanced non-small cell lung cancer: a real-world, retrospective bicenter cohort study'.","authors":"Xudong Zhu","doi":"10.1136/jitc-2025-011845","DOIUrl":"10.1136/jitc-2025-011845","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer.","authors":"Hyein Jeong, Jaemoon Koh, Sehui Kim, Jeemin Yim, Seung Geun Song, Hanbyeol Kim, Yingying Li, Soo Hyun Lee, Yeon Kyu Chung, Hongsoon Kim, Chul-Hwan Lee, Hye Young Kim, Bhumsuk Keam, Se-Hoon Lee, Doo Hyun Chung, Yoon Kyung Jeon","doi":"10.1136/jitc-2024-010612","DOIUrl":"10.1136/jitc-2024-010612","url":null,"abstract":"<p><strong>Background: </strong>Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression.</p><p><strong>Methods: </strong>Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade.</p><p><strong>Results: </strong>In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-β, TNF-α, IL-1β) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B⁺ or IFNγ⁺ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B⁺ or IFNγ⁺ CD8 T-cells.</p><p><strong>Conclusions: </strong>The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade.","authors":"Jade Moore, Jim Gkantalis, Ines Guix, William Chou, Kobe Yuen, Ann A Lazar, Matthew Spitzer, Alexis Combes, Mary Helen Barcellos-Hoff","doi":"10.1136/jitc-2024-010528","DOIUrl":"10.1136/jitc-2024-010528","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGFβ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response.</p><p><strong>Methods: </strong>We analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high βAlt, a score representing low expression of a signature consisting of TGFβ targets and high expression of genes involved in error-prone DNA repair. The immune context of βAlt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control.</p><p><strong>Results: </strong>We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB.</p><p><strong>Conclusions: </strong>These studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic and predictive values of a multimodal nomogram incorporating tumor and peritumor morphology with immune status in resectable lung adenocarcinoma.","authors":"Huan Lin, Junjie Hua, Yumeng Wang, Mingwei Chen, Yanting Liang, LiXu Yan, Wei Zhao, Shiwei Luo, Deqing Hong, Xin Chen, Xipeng Pan, Jun Liu, Zaiyi Liu","doi":"10.1136/jitc-2024-010723","DOIUrl":"10.1136/jitc-2024-010723","url":null,"abstract":"<p><strong>Background: </strong>Current prognostic and predictive biomarkers for lung adenocarcinoma (LUAD) predominantly rely on unimodal approaches, limiting their characterization ability. There is an urgent need for a comprehensive and accurate biomarker to guide individualized adjuvant therapy decisions.</p><p><strong>Methods: </strong>In this retrospective study, data from patients with resectable LUAD (stage I-III) were collected from two hospitals and a publicly available dataset, forming a training dataset (n=223), a validation dataset (n=95), a testing dataset (n=449), and the non-small cell lung cancer (NSCLC) Radiogenomics dataset (n=59). Tumor and peritumor scores were constructed from preoperative CT radiomics features (shape/intensity/texture). An immune score was derived from the density of tumor-infiltrating lymphocytes (TILs) within the cancer epithelium and stroma on hematoxylin and eosin-stained whole-slide images. A clinical score was constructed based on clinicopathological risk factors. A Cox regression model was employed to integrate these scores, thereby constructing a multimodal nomogram to predict disease-free survival (DFS). The adjuvant chemotherapy benefit rate was subsequently calculated based on this nomogram.</p><p><strong>Results: </strong>The multimodal nomogram outperformed each of the unimodal scores in predicting DFS, with a C-index of 0.769 (vs 0.634-0.731) in the training dataset, 0.730 (vs 0.548-0.713) in the validation dataset, and 0.751 (vs 0.660-0.692) in the testing dataset. It was independently associated with DFS after adjusting for other clinicopathological risk factors (training dataset: HR=3.02, p<0.001; validation dataset: HR=2.33, p<0.001; testing dataset: HR=2.03, p=0.001). The adjuvant chemotherapy benefit rate effectively distinguished between patients benefiting from adjuvant chemotherapy and those from observation alone (interaction p<0.001). Furthermore, the high-/low-risk groups defined by the multimodal nomogram provided refined stratification of candidates for adjuvant chemotherapy identified by current guidelines (p<0.001). Gene set enrichment analyses using the NSCLC Radiogenomics dataset revealed associations between tumor/peritumor scores and pathways involved in epithelial-mesenchymal transition, angiogenesis, IL6-JAK-STAT3 signaling, and reactive oxidative species.</p><p><strong>Conclusion: </strong>The multimodal nomogram, which incorporates tumor and peritumor morphology with anti-tumor immune response, provides superior prognostic accuracy compared with unimodal scores. Its defined adjuvant chemotherapy benefit rates can inform individualized adjuvant therapy decisions.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1^IR2 promotes tumor evasion via deregulating CD8⁺ T cell function.","authors":"Haojing Zang, Tongfeng Liu, Xiaodong Wang, Shuwen Cheng, Xiaofeng Zhu, Chang Huang, Liqiang Duan, Xujie Zhao, Fang Guo, Xuetong Wang, Chang Zhang, Facai Yang, Yinmin Gu, Hongbo Hu, Shan Gao","doi":"10.1136/jitc-2024-010529","DOIUrl":"10.1136/jitc-2024-010529","url":null,"abstract":"<p><strong>Background: </strong>The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether <i>PDCD1</i> encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion.</p><p><strong>Methods: </strong>An AS isoform of human <i>PDCD1</i>, characterized by the second IR and named PD-1^IR2, was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1^IR2 was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. <i>PDCD1^IR2</i> ^<i>CKI</i> mice which specifically conditional knock-in <i>PDCD1^IR2</i> in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1^IR2 in vivo.</p><p><strong>Results: </strong>PD-1^IR2 is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1^IR2 expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1^IR2 negatively regulates the immune function of CD8⁺ T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1^IR2+ CD8⁺ T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1^IR2 mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice.</p><p><strong>Conclusions: </strong>PD-1^IR2 is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: Correspondence on \"Hyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL-15\" by Ataca Atilla and Atilla.","authors":"Gengwen Tian, Amy N Courtney, Andras Heczey, Leonid S Metelitsa","doi":"10.1136/jitc-2025-011858","DOIUrl":"10.1136/jitc-2025-011858","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}