Oncoimmunology最新文献

{"title":"Non-pharmaceutical interventions to optimize cancer immunotherapy.","authors":"Maximilian Boesch,&nbsp;Florent Baty,&nbsp;Frank Rassouli,&nbsp;Tobias Kowatsch,&nbsp;Markus Joerger,&nbsp;Martin Früh,&nbsp;Martin H Brutsche","doi":"10.1080/2162402X.2023.2255459","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2255459","url":null,"abstract":"<p><p>The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one's own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable <i>per se</i>, at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e9/70/KONI_12_2255459.PMC10543347.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41137485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Listeria-based vaccination against the pericyte antigen RGS5 elicits anti-vascular effects and colon cancer protection.","authors":"Trevor S Anderson, Amanda L McCormick, Elizabeth A Daugherity, Mariam Oladejo, Izuchukwu F Okpalanwaka, Savanna L Smith, Duke Appiah, Laurence M Wood, Devin B Lowe","doi":"10.1080/2162402X.2023.2260620","DOIUrl":"10.1080/2162402X.2023.2260620","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality despite efforts to improve standard interventions. As CRC patients can benefit from immunotherapeutic strategies that incite effector T cell action, cancer vaccines represent a safe and promising therapeutic approach to elicit protective and durable immune responses against components of the tumor microenvironment (TME). In this study, we investigate the pre-clinical potential of a <i>Listeria monocytogenes</i> (Lm)-based vaccine targeting the CRC-associated vasculature. CRC survival and progression are reliant on functioning blood vessels to effectively mediate various metabolic processes and oxygenate underlying tissues. We, therefore, advance the strategy of initiating immunity in syngeneic mouse models against the endogenous pericyte antigen RGS5, which is a critical mediator of pathological vascularization. Overall, Lm-based vaccination safely induced potent anti-tumor effects that consisted of recruiting functional Type-1-associated T cells into the TME and reducing tumor blood vessel content. This study underscores the promising clinical potential of targeting RGS5 against vascularized tumors like CRC.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4a/10/KONI_12_2260620.PMC10540654.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41140117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy.","authors":"Sandra Martinez-Morilla, Myrto Moutafi, Aileen I Fernandez, Shlomit Jessel, Prajan Divakar, Pok Fai Wong, Rolando Garcia-Milian, Kurt A Schalper, Harriet M Kluger, David L Rimm","doi":"10.1080/2162402X.2023.2260618","DOIUrl":"10.1080/2162402X.2023.2260618","url":null,"abstract":"<p><p>Although immune checkpoint inhibitor (ICI) therapy has dramatically improved outcome for metastatic melanoma patients, many patients do not benefit. Since adverse events may be severe, biomarkers for resistance would be valuable, especially in the adjuvant setting. We performed high-plex digital spatial profiling (DSP) using the NanoString GeoMx® on 53 pre-treatment specimens from ICI-treated metastatic melanoma cases. We interrogated 77 targets simultaneously in four molecular compartments defined by S100B for tumor, CD68 for macrophages, CD45 for leukocytes, and nonimmune stromal cells defined as regions negative for all three compartment markers but positive for SYTO 13. For DSP validation, we confirmed the results obtained for some immune markers, such as CD8, CD4, CD20, CD68, CD45, and PD-L1, by quantitative immunofluorescence (QIF). In the univariable analysis, 38 variables were associated with outcome, 14 of which remained significant after multivariable adjustment. Among them, CD95 was further validated using multiplex immunofluorescence in the Discovery immunotherapy (ITX) Cohort and an independent validation cohort with similar characteristics, showing an association between high levels of CD95 and shorter progression-free survival. We found that CD95 in stroma was associated with resistance to ICI. With further validation, this biomarker could have value to select patients that will not benefit from immunotherapy.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fc/dc/KONI_12_2260618.PMC10540659.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41146673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PB101, a VEGF- and PlGF-targeting decoy protein, enhances antitumor immunity and suppresses tumor progression and metastasis.","authors":"Eun-Jin Go,&nbsp;Hannah Yang,&nbsp;Seung Joon Lee,&nbsp;Hyun Gul Yang,&nbsp;Jin A Shin,&nbsp;Won Suk Lee,&nbsp;Hye Seong Lim,&nbsp;Hong Jae Chon,&nbsp;Chan Kim","doi":"10.1080/2162402X.2023.2259212","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2259212","url":null,"abstract":"<p><p>Antiangiogenic therapy is a recognized method for countering the immunosuppressive tumor microenvironment (TME) and improving anti-tumor immunity. PB101 is a glycosylated decoy receptor that binds to VEGF-A and PlGF with high affinity, based on the VEGFR1 backbone. Here, we elucidated PB101-induced remodeling of tumor angiogenesis and immunity, which enhances anti-PD-L1 immune checkpoint blockade. PB101 inhibited tumor growth by suppressing angiogenesis and enhancing CD8⁺ T cell infiltration into the tumors. PB101 induced robust reprogramming of antitumor immunity and activates intratumoral CD8⁺ T cells. Anti-tumor efficacy of PB101 is mostly dependent on CD8⁺ T cells and IFN-γ. PB101 reprograms tumor immunity in a manner distinct from that of the conventional VEGF decoy receptor, VEGF-trap. With its potent immune-modulating capability, PB101 synergizes with an anti-PD-L1, triggering strengthened antitumor immunity. Combining PB101 and anti-PD-L1 could establish durable protective immunity against tumor recurrence and metastasis. The findings of this study offer scientific rationales for further clinical development of PB101, particularly when used in combination with immune checkpoint inhibitors, as a potential treatment for advanced cancers.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/88/09/KONI_12_2259212.PMC10515676.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41168339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoimmunotherapy triggers immune responses targeting microsatellite stable colorectal cancer.","authors":"Marion Thibaudin,&nbsp;Francois Ghiringhelli","doi":"10.1080/2162402X.2023.2257098","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2257098","url":null,"abstract":"<p><p>Checkpoint blockade immunotherapy transforms many types of cancer; however, in the field of metastatic colorectal cancer, checkpoint blockers are only effective in microsatellite-unstable tumors, which represent only a minority of patients. Microsatellite-stable tumors are thought to be immunoresistant. A recent publication demonstrates that, contrary to the standard view point, the combination of chemo-immunotherapy could trigger a tumor-specific immune response, leading to clinical benefit.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6b/14/KONI_12_2257098.PMC10506430.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41147687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD40 agonism improves anti-tumor T cell priming induced by the combination of radiation therapy plus CTLA4 inhibition and enhances tumor response.","authors":"Maud Charpentier,&nbsp;Silvia Formenti,&nbsp;Sandra Demaria","doi":"10.1080/2162402X.2023.2258011","DOIUrl":"https://doi.org/10.1080/2162402X.2023.2258011","url":null,"abstract":"<p><p>Radiation therapy (RT) combined with CTLA4 blockers converts immunosuppressed (cold) mouse triple negative breast cancers (TNBCs) into immune infiltrated (hot) lesions. We have recently shown that targeting the myeloid compartment to improve dendritic cell activation is required for most TNBC-bearing mice to achieve superior therapeutic responses to RT plus CTLA4 inhibitors.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/78/KONI_12_2258011.PMC10506429.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41129626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.","authors":"Annalisa Adamo,&nbsp;Cristina Frusteri,&nbsp;Sara Pilotto,&nbsp;Simone Caligola,&nbsp;Lorenzo Belluomini,&nbsp;Ornella Poffe,&nbsp;Luca Giacobazzi,&nbsp;Silvia Dusi,&nbsp;Chiara Musiu,&nbsp;Yushu Hu,&nbsp;Tian Wang,&nbsp;Davide Rizzini,&nbsp;Antonio Vella,&nbsp;Stefania Canè,&nbsp;Giulia Sartori,&nbsp;Jessica Insolda,&nbsp;Marco Sposito,&nbsp;Ursula Cesta Incani,&nbsp;Carmine Carbone,&nbsp;Geny Piro,&nbsp;Francesca Pettinella,&nbsp;Fang Qi,&nbsp;Dali Wang,&nbsp;Silvia Sartoris,&nbsp;Francesco De Sanctis,&nbsp;Patrizia Scapini,&nbsp;Stefano Dusi,&nbsp;Marco Antonio Cassatella,&nbsp;Emilio Bria,&nbsp;Michele Milella,&nbsp;Vincenzo Bronte,&nbsp;Stefano Ugel","doi":"10.1080/2162402X.2023.2253644","DOIUrl":"10.1080/2162402X.2023.2253644","url":null,"abstract":"<p><p>Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as <i>progressors</i> (P) or <i>non-progressors</i> (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using <i>t</i>-distributed stochastic neighbor embedding (<i>t</i>-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dc/c9/KONI_12_2253644.PMC10503454.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10309663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.","authors":"David Henault,&nbsp;David Stephen,&nbsp;Pierre-Antoine St-Hilaire,&nbsp;Nouredin Messaoudi,&nbsp;Franck Vandenbroucke-Menu,&nbsp;Eve Simoneau,&nbsp;Zhixia Rong,&nbsp;Marylène Plasse,&nbsp;Richard Létourneau,&nbsp;André Roy,&nbsp;Michel Dagenais,&nbsp;Réal Lapointe,&nbsp;Bich Nguyen,&nbsp;Anne-Marie Mes-Masson,&nbsp;G Soucy,&nbsp;Simon Turcotte","doi":"10.1080/2162402X.2023.2253642","DOIUrl":"10.1080/2162402X.2023.2253642","url":null,"abstract":"<p><p>In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3⁺ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, <i>p</i> = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, <i>p</i> = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10309660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro vascular differentiation system efficiently produces natural killer cells for cancer immunotherapies.","authors":"Yekaterina Galat, Yuchen Du, Mariana Perepitchka, Xiao-Nan Li, Irina V Balyasnikova, William T Tse, Svetlana Dambaeva, Sylvia Schneiderman, Philip M Iannaccone, Oren Becher, Douglas K Graham, Vasiliy Galat","doi":"10.1080/2162402X.2023.2240670","DOIUrl":"10.1080/2162402X.2023.2240670","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapeutic innovation is crucial for limited operability tumors. CAR T-cell therapy displayed reduced efficiency against glioblastoma (GBM), likely due to mutations underlying disease progression. Natural Killer cells (NKs) detect cancer cells despite said mutations - demonstrating increased tumor elimination potential. We developed an NK differentiation system using human pluripotent stem cells (hPSCs). Via this system, genetic modifications targeting cancer treatment challenges can be introduced during pluripotency - enabling unlimited production of modified \"off-the-shelf\" hPSC-NKs.</p><p><strong>Methods: </strong>hPSCs were differentiated into hematopoietic progenitor cells (HPCs) and NKs using our novel organoid system. These cells were characterized using flow cytometric and bioinformatic analyses. HPC engraftment potential was assessed using NSG mice. NK cytotoxicity was validated using <i>in vitro</i> and <i>in vitro</i> K562 assays and further corroborated on lymphoma, diffuse intrinsic pontine glioma (DIPG), and GBM cell lines <i>in vitro</i>.</p><p><strong>Results: </strong>HPCs demonstrated engraftment in peripheral blood samples, and hPSC-NKs showcased morphology and functionality akin to same donor peripheral blood NKs (PB-NKs). The hPSC-NKs also displayed potential advantages regarding checkpoint inhibitor and metabolic gene expression, and demonstrated <i>in</i> <i>vitro</i> and <i>in</i> <i>vivo</i> cytotoxicity against various cancers.</p><p><strong>Conclusions: </strong>Our organoid system, designed to replicate <i>in</i> <i>vivo</i> cellular organization (including signaling gradients and shear stress conditions), offers a suitable environment for HPC and NK generation. The engraftable nature of HPCs and potent NK cytotoxicity against leukemia, lymphoma, DIPG, and GBM highlight the potential of this innovative system to serve as a valuable tool that will benefit cancer treatment and research - improving patient survival and quality of life.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/95/95/KONI_12_2240670.PMC10501168.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10309664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells.","authors":"Xin Jin,&nbsp;Danni Xie,&nbsp;Rui Sun,&nbsp;Wenyi Lu,&nbsp;Xia Xiao,&nbsp;Yibing Yu,&nbsp;Juanxia Meng,&nbsp;Mingfeng Zhao","doi":"10.1080/2162402X.2023.2248826","DOIUrl":"10.1080/2162402X.2023.2248826","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cells have not made significant progress in the treatment of acute myeloid leukemia (AML) in earlyclinical studies. This lack of progress could be attributed in part to the immunosuppressive microenvironment of AML, such as monocyte-like myeloid-derived suppressor cells (M-MDSCs) and alternatively activated macrophages (M2 cells), which can inhibit the antitumor activity of CAR-T cells. Furthermore, AML cells are usually heterogeneous, and single-target CAR-T cells may not be able to eliminate all AML cells, leading to disease relapse. CD123 and NKG2D ligands (NKG2DLs) are commonly used targets for CAR-T therapy of AML, and M-MDSCs and M2 cells express both antigens. We developed dual-targeted CAR-T (123NL CAR-T) cells targeting CD123 and NKG2DL by various structural optimization screens. Our study reveals that 123NL CAR-T cells eradicate AML cells and selectively target immunosuppressive cells. A highly compact marker/suicide gene, RQR8, which binds targeting epitopes of CD34 and CD20 antigens, was also incorporated in front of the CAR structure. The binding of Rituximab to RQR8 leads to the elimination of 123NL CAR-T cells and cessation of their cytotoxicity. In conclusion, we successfully developed dual effects of 123NL CAR-T cells against tumor cells and immunosuppressive cells, which can avoid target escape and resist the effects of immunosuppressive microenvironment.</p>","PeriodicalId":19683,"journal":{"name":"Oncoimmunology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2023-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/03/e8/KONI_12_2248826.PMC10461507.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}