Colt A Egelston, Weihua Guo, Diana L Simons, Jian Ye, Christian Avalos, Shawn T Solomon, Mary Nwangwu, Michael S Nelson, Jiayi Tan, Eliza R Bacon, Kena Ihle, Daniel Schmolze, Lusine Tumyan, James R Waisman, Peter P Lee
{"title":"Organ-Specific Immune Setpoints Underlie Divergent Immune Profiles across Metastatic Sites in Breast Cancer.","authors":"Colt A Egelston, Weihua Guo, Diana L Simons, Jian Ye, Christian Avalos, Shawn T Solomon, Mary Nwangwu, Michael S Nelson, Jiayi Tan, Eliza R Bacon, Kena Ihle, Daniel Schmolze, Lusine Tumyan, James R Waisman, Peter P Lee","doi":"10.1158/2326-6066.CIR-23-0718","DOIUrl":"10.1158/2326-6066.CIR-23-0718","url":null,"abstract":"<p><p>Immune composition within the tumor microenvironment (TME) plays a central role in the propensity of cancer cells to metastasize and respond to therapy. Previous studies have suggested that the metastatic TME is immune-suppressed. However, limited accessibility to multiple metastatic sites within patients has made assessing the immune TME difficult in the context of multiorgan metastases. We utilized a rapid postmortem tissue collection protocol to assess the immune composition of numerous sites of breast cancer metastasis and paired tumor-free tissues. Metastases had comparable immune cell densities and compositions to paired tumor-free tissues of the same organ type. In contrast, immune cell densities in both metastatic and tumor-free tissues differed significantly between organ types, with lung immune infiltration being consistently greater than that in the liver. These immune profiling results were consistent between flow cytometry and multiplex immunofluorescence-based spatial analysis. Furthermore, we found that granulocytes were the predominant tumor-infiltrating immune cells in lung and liver metastases, and these granulocytes comprised most PD-L1-expressing cells in many tissue sites. We also identified distinct potential mechanisms of immunosuppression in lung and liver metastases, with the lung having increased expression of PD-L1+ antigen-presenting cells and the liver having higher numbers of activated regulatory T cells and HLA-DRlow monocytes. Together, these results demonstrate that the immune contexture of metastases is dictated by organ type and that immunotherapy strategies may benefit from unique tailoring to the tissue-specific features of the immune TME.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1559-1573"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757319","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}
Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang
{"title":"Tumor-Associated Antigen Burden Correlates with Immune Checkpoint Blockade Benefit in Tumors with Low Levels of T-cell Exhaustion.","authors":"Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang","doi":"10.1158/2326-6066.CIR-23-0932","DOIUrl":"10.1158/2326-6066.CIR-23-0932","url":null,"abstract":"<p><p>Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1589-1602"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970677","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}
Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Levi M Mangarin, Valeria Estrada Nevarro, Nezar Mehanna, Jonathan F Khan, Divya Venkatesh, Daniel Thach, Neal Rosen, Jedd D Wolchok, Taha Merghoub
{"title":"Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models.","authors":"Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Levi M Mangarin, Valeria Estrada Nevarro, Nezar Mehanna, Jonathan F Khan, Divya Venkatesh, Daniel Thach, Neal Rosen, Jedd D Wolchok, Taha Merghoub","doi":"10.1158/2326-6066.CIR-23-0729","DOIUrl":"10.1158/2326-6066.CIR-23-0729","url":null,"abstract":"<p><p>MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1392-1408"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417944","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}
Priyanka Yolmo, Sadaf Rahimi, Stephen Chenard, Gwenaëlle Conseil, Danielle Jenkins, Kartik Sachdeva, Isaac Emon, Jake Hamilton, Minqi Xu, Manu Rangachari, Eva Michaud, Jose J Mansure, Wassim Kassouf, David M Berman, David R Siemens, Madhuri Koti
{"title":"Atypical B Cells Promote Cancer Progression and Poor Response to Bacillus Calmette-Guérin in Non-Muscle Invasive Bladder Cancer.","authors":"Priyanka Yolmo, Sadaf Rahimi, Stephen Chenard, Gwenaëlle Conseil, Danielle Jenkins, Kartik Sachdeva, Isaac Emon, Jake Hamilton, Minqi Xu, Manu Rangachari, Eva Michaud, Jose J Mansure, Wassim Kassouf, David M Berman, David R Siemens, Madhuri Koti","doi":"10.1158/2326-6066.CIR-23-1114","DOIUrl":"10.1158/2326-6066.CIR-23-1114","url":null,"abstract":"<p><p>Poor response to Bacillus Calmette-Guérin (BCG) immunotherapy remains a major barrier in the management of patients with non-muscle invasive bladder cancer (NMIBC). Multiple factors are associated with poor outcomes, including biological aging and female sex. More recently, it has emerged that a B-cell-infiltrated pretreatment immune microenvironment of NMIBC tumors can influence the response to intravesically administered BCG. The mechanisms underlying the roles of B cells in NMIBC are poorly understood. Here, we show that B-cell-dominant tertiary lymphoid structures (TLSs), a hallmark feature of the chronic mucosal immune response, are abundant and located close to the epithelial compartment in pretreatment tumors from BCG non-responders. Digital spatial proteomic profiling of whole tumor sections from male and female patients with NMIBC who underwent treatment with intravesical BCG, revealed higher expression of immune exhaustion-associated proteins within the tumor-adjacent TLSs in both responders and non-responders. Chronic local inflammation, induced by the N-butyl-N-(4-hydroxybutyl) nitrosamine carcinogen, led to TLS formation with recruitment and differentiation of the immunosuppressive atypical B-cell (ABC) subset within the bladder microenvironment, predominantly in aging female mice compared to their male counterparts. Depletion of ABCs simultaneous to BCG treatment delayed cancer progression in female mice. Our findings provide evidence indicating a role for ABCs in BCG response and will inform future development of therapies targeting the B-cell-exhaustion axis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1320-1339"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445692","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}
Winson Cai, Kento Tanaka, Xiaoli Mi, Vinagolu K Rajasekhar, Jonathan F Khan, Sarah Yoo, Elisa de Stanchina, Jahan Rahman, Serena Mathew, Parwiz Abrahimi, Sydney Souness, Terence J Purdon, James R McDowell, Jeremy Meyerberg, Takeshi Fujino, John H Healey, Omar Abdel-Wahab, David A Scheinberg, Renier J Brentjens, Anthony F Daniyan
{"title":"Augmenting CAR T-cell Functions with LIGHT.","authors":"Winson Cai, Kento Tanaka, Xiaoli Mi, Vinagolu K Rajasekhar, Jonathan F Khan, Sarah Yoo, Elisa de Stanchina, Jahan Rahman, Serena Mathew, Parwiz Abrahimi, Sydney Souness, Terence J Purdon, James R McDowell, Jeremy Meyerberg, Takeshi Fujino, John H Healey, Omar Abdel-Wahab, David A Scheinberg, Renier J Brentjens, Anthony F Daniyan","doi":"10.1158/2326-6066.CIR-24-0246","DOIUrl":"10.1158/2326-6066.CIR-24-0246","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success in the treatment of B-cell malignancies. However, its clinical efficacy in solid tumors is limited, primarily by target antigen heterogeneity. To overcome antigen heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand of both lymphotoxin-β receptor on cancer cells and herpes virus entry mediator on immune cells. LIGHT-expressing CAR T cells displayed both antigen-directed cytotoxicity mediated by the CAR and antigen-independent killing mediated through the interaction of LIGHT with lymphotoxin-β receptor on cancer cells. Moreover, CAR T cells expressing LIGHT had immunostimulatory properties that improved the cells' proliferation and cytolytic profile. These data indicate that LIGHT-expressing CAR T cells may provide a way to eliminate antigen-negative tumor cells to prevent antigen-negative disease relapse.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1361-1379"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497234","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}
Daniel Constantin, Vladimir Nosi, Natalie Kehrer, Alessandro Vacchini, Andrew Chancellor, Emmanuel Contassot, Aisha Beshirova, Gennaro Prota, Alexander Navarini, Lucia Mori, Gennaro De Libero
{"title":"MR1 Gene and Protein Expression Are Enhanced by Inhibition of the Extracellular Signal-Regulated Kinase ERK.","authors":"Daniel Constantin, Vladimir Nosi, Natalie Kehrer, Alessandro Vacchini, Andrew Chancellor, Emmanuel Contassot, Aisha Beshirova, Gennaro Prota, Alexander Navarini, Lucia Mori, Gennaro De Libero","doi":"10.1158/2326-6066.CIR-24-0110","DOIUrl":"10.1158/2326-6066.CIR-24-0110","url":null,"abstract":"<p><p>The MHC class I-related molecule MR1 is ubiquitously expressed, is highly conserved among mammals, and presents bacterial and endogenous antigens in tumor cells. These features indicate that tumor-specific T cells restricted to MR1 may represent ideal candidates for novel cancer-directed T-cell immunotherapy. The very low expression of the MR1 protein at the cell surface is a potential challenge limiting the possible use of MR1-directed immunotherapies. To overcome this challenge, it is important that understanding of the mechanisms regulating MR1 expression is increased, as little is known about this currently. This study identified ERK1/2 as negative regulators of the MR1 gene and protein expression. Inhibition of ERK1/2 in tumor cells or treatment of BRAF-mutant tumor cells with drugs specific for mutated BRAF increased MR1 protein expression and recognition by tumor-reactive and MR1-restricted T cells. The ERK1/2 inhibition of MR1 was mediated by the ELF1 transcription factor, which was required for MR1 gene expression. The effects of ERK1/2 inhibition also occurred in cancer cell lines of different tissue origins, cancer cell lines resistant to drugs that inhibit mutated BRAF, and primary cancer cells, making them potential targets of specific T cells. In contrast to tumor cells, the recognition of healthy cells was very poor or absent after ERK1/2 inhibition. These findings suggest a pharmaceutical approach to increase MR1 protein expression in tumor cells and the subsequent activation of MR1-restricted T cells, and they have potential therapeutic implications.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1452-1467"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726946","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}
Tianyi Liu, Dan Jin, Son B Le, Dongjiang Chen, Mathew Sebastian, Alberto Riva, Ruixuan Liu, David D Tran
{"title":"Machine Learning-Directed Conversion of Glioblastoma Cells to Dendritic Cell-Like Antigen-Presenting Cells as Cancer Immunotherapy.","authors":"Tianyi Liu, Dan Jin, Son B Le, Dongjiang Chen, Mathew Sebastian, Alberto Riva, Ruixuan Liu, David D Tran","doi":"10.1158/2326-6066.CIR-23-0721","DOIUrl":"10.1158/2326-6066.CIR-23-0721","url":null,"abstract":"<p><p>Immunotherapy has limited efficacy in glioblastoma (GBM) due to the blood-brain barrier and the immunosuppressed or \"cold\" tumor microenvironment (TME) of GBM, which is dominated by immune-inhibitory cells and depleted of CTL and dendritic cells (DC). Here, we report the development and application of a machine learning precision method to identify cell fate determinants (CFD) that specifically reprogram GBM cells into induced antigen-presenting cells with DC-like functions (iDC-APC). In murine GBM models, iDC-APCs acquired DC-like morphology, regulatory gene expression profile, and functions comparable to natural DCs. Among these acquired functions were phagocytosis, direct presentation of endogenous antigens, and cross-presentation of exogenous antigens. The latter endowed the iDC-APCs with the ability to prime naïve CD8+ CTLs, a hallmark DC function critical for antitumor immunity. Intratumor iDC-APCs reduced tumor growth and improved survival only in immunocompetent animals, which coincided with extensive infiltration of CD4+ T cells and activated CD8+ CTLs in the TME. The reactivated TME synergized with an intratumor soluble PD1 decoy immunotherapy and a DC-based GBM vaccine, resulting in robust killing of highly resistant GBM cells by tumor-specific CD8+ CTLs and significantly extended survival. Lastly, we defined a unique CFD combination specifically for the human GBM to iDC-APC conversion of both glioma stem-like cells and non-stem-like cell GBM cells, confirming the clinical utility of a computationally directed, tumor-specific conversion immunotherapy for GBM and potentially other solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1340-1360"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757318","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}
Bowen Dong, Nataša Obermajer, Takemasa Tsuji, Junko Matsuzaki, Cindy M Bonura, Cindy Sander, Henry Withers, Mark D Long, Colin Chavel, Scott H Olejniczak, Hans Minderman, John M Kirkwood, Robert P Edwards, Walter J Storkus, Pedro Romero, Pawel Kalinski
{"title":"NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.","authors":"Bowen Dong, Nataša Obermajer, Takemasa Tsuji, Junko Matsuzaki, Cindy M Bonura, Cindy Sander, Henry Withers, Mark D Long, Colin Chavel, Scott H Olejniczak, Hans Minderman, John M Kirkwood, Robert P Edwards, Walter J Storkus, Pedro Romero, Pawel Kalinski","doi":"10.1158/2326-6066.CIR-24-0061","DOIUrl":"10.1158/2326-6066.CIR-24-0061","url":null,"abstract":"<p><p>Cytotoxic CD8+ T lymphocyte (CTL) recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells and also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival of patients with melanoma. Using MART1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior co-stimulatory effects of DNAM1 over CD28 involved enhanced TCR signaling, CTL killer function, and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in antigen specificity and selectivity of killer function. In addition, the elevation of NKR ligand expression on cancer cells due to chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAAs. Our data help explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T-cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1421-1437"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466383","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}
Daniel Peters, Lena M Kranz, David Eisel, Mustafa Diken, Sebastian Kreiter, Özlem Türeci, Ugur Sahin, Mathias Vormehr
{"title":"RNA-encoded Interleukin 2 with Extended Bioavailability Amplifies RNA Vaccine-Induced Antitumor T-cell Immunity.","authors":"Daniel Peters, Lena M Kranz, David Eisel, Mustafa Diken, Sebastian Kreiter, Özlem Türeci, Ugur Sahin, Mathias Vormehr","doi":"10.1158/2326-6066.CIR-23-0701","DOIUrl":"10.1158/2326-6066.CIR-23-0701","url":null,"abstract":"<p><p>Interleukin 2 (IL-2) is a crucial cytokine in T-cell immunity, with a promising potential in cancer vaccines. However, therapeutic application of IL-2 is hampered by its short half-life and substantial toxicity. This study reports preclinical characterization of a mouse serum albumin-IL-2 fusion protein (Alb-IL2) encoded on nucleoside-modified RNA that is delivered via a nanoparticle formulation (Alb-IL2 RNA-NP) mediating prolonged cytokine availability. Alb-IL2 RNA-NP was combined with RNA-lipoplex (RNA-LPX) vaccines to evaluate its effect on the expansion of vaccine-induced antigen specific T-cell immunity. In mice dosed with Alb-IL2 RNA-NP, translated protein was shown to be systemically available up to 2 days, with an albumin-dependent preferred presence in the tumor and tumor-draining lymph node. Alb-IL2 RNA-NP administration prolonged serum availability of the cytokine compared with murine recombinant IL-2. In combination with RNA-LPX vaccines, Alb-IL2 RNA-NP administration highly increased the expansion of RNA-LPX vaccine-induced CD8+ T cells in the spleen and blood. The combination enhanced and sustained the fraction of IL-2 receptor (IL-2R) α-positive antigen-specific CD8+ T cells and ameliorated the functional capacity of the CD8+ T-cell population. Alb-IL2 RNA-NP strongly improved the antitumor activity and survival of concomitant RNA-LPX vaccination and PD-L1 blockade in a subcutaneous mouse tumor model. The favorable pharmacokinetic properties of Alb-IL2 RNA-NP render it an attractive modality for rationally designed combination immunotherapy. RNA vaccines that induce tumor-specific T-cell immunity for Alb-IL2 RNA-NP to further amplify are particularly attractive combination partners.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1409-1420"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417946","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}
Vasyl Eisenberg, Shiran Hoogi, Erel Katzman, Nimrod Ben Haim, Raphaelle Zur-Toledano, Maria Radman, Yishai Reboh, Oranit Zadok, Iris Kamer, Jair Bar, Irit Sagi, Ayal Hendel, Cyrille J Cohen
{"title":"Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells.","authors":"Vasyl Eisenberg, Shiran Hoogi, Erel Katzman, Nimrod Ben Haim, Raphaelle Zur-Toledano, Maria Radman, Yishai Reboh, Oranit Zadok, Iris Kamer, Jair Bar, Irit Sagi, Ayal Hendel, Cyrille J Cohen","doi":"10.1158/2326-6066.CIR-23-0823","DOIUrl":"10.1158/2326-6066.CIR-23-0823","url":null,"abstract":"<p><p>Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation. Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies. We focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9+ T-cell population displayed reduced effector function. We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system enhanced the functionality of primary human T cells. Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation. Thus, we designed several Siglec-9-based chimeric switch receptors (CSR), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen-specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers. Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors. Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell-based cancer treatment. See related Spotlight by Abken, p. 1310.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1380-1391"},"PeriodicalIF":8.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733568","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}
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