Saumya Jani, Tomas Bencomo, Carolyn Shasha, Thomas Pulliam, Ana Jojic, Candice D Church, Ted A Gooley, David M Koelle, Evan W Newell, Paul Nghiem
{"title":"Circulating neoantigen- and viral oncoprotein-specific CD8+ T cells share a transcriptional signature.","authors":"Saumya Jani, Tomas Bencomo, Carolyn Shasha, Thomas Pulliam, Ana Jojic, Candice D Church, Ted A Gooley, David M Koelle, Evan W Newell, Paul Nghiem","doi":"10.1158/2326-6066.CIR-25-0082","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0082","url":null,"abstract":"<p><p>Tumor-specific CD8+ T cells in blood appear to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, identification of tumor-specific CD8+ T cells is not routinely feasible. Here, we characterized polyomavirus-specific CD8+ T cells from blood of 17 patients with virus-driven Merkel cell carcinoma (MCC). We identified a 98-gene signature, SPoTT (Signature of Peripheral Tumor-specific CD8+ T cells), that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus from tumor. In validation cohorts of MCC, as well as neoantigen-driven cancers, SPoTT was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCR_PBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize MCPyV-specific T cells with sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally-driven cancers.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343723","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}
Myriam Ben Khelil, Maxime Fredon, Nawfel Adib, Adeline Bouard, Marie Perchaud, Syrine Abdeljaoued, Charles-Frédéric Mantion, Kamal Asgarov, Philippe Guillaume, Laurie Spehner, Evan Seffar, Marjorie Labesse, Angélique Vienot, Virginie Mougey, Mathieu Gonçalves-Venturelli, Sara Bobisse, Alexandre Harari, Camilla Jandus, Francine Garnache-Ottou, Delphine Binda, Olivier Adotévi, Yann Godet, Marie Kroemer, Christophe Borg, Romain Loyon
{"title":"Targeting SALL4 with an HLA Class I-restricted TCR for cancer immunotherapy.","authors":"Myriam Ben Khelil, Maxime Fredon, Nawfel Adib, Adeline Bouard, Marie Perchaud, Syrine Abdeljaoued, Charles-Frédéric Mantion, Kamal Asgarov, Philippe Guillaume, Laurie Spehner, Evan Seffar, Marjorie Labesse, Angélique Vienot, Virginie Mougey, Mathieu Gonçalves-Venturelli, Sara Bobisse, Alexandre Harari, Camilla Jandus, Francine Garnache-Ottou, Delphine Binda, Olivier Adotévi, Yann Godet, Marie Kroemer, Christophe Borg, Romain Loyon","doi":"10.1158/2326-6066.CIR-24-0207","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0207","url":null,"abstract":"<p><p>Aberrant expression of the oncogene SALL4 is associated with stemness, more aggressive cancer phenotype, and reduced patient survival in various tumor types making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer (CRC) tissues and demonstrated that SALL4 was overexpressed in primary tumor and paired liver metastasis. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of gastrointestinal cancer patients whereas no responses were observed for the peripheral blood of healthy donors. Thereafter, we isolated a SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328244","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}
Chuwei Liu, Heng Liang, Peipei Wang, Min Xiao, Yuyan Zheng, Shijia Yan, Yuan Deng, Ruonian Liu, Arabella H Wan, Zhi Wang, Xiongbin Lu, Wu Song, Weiling He, Guohui Wan
{"title":"HNRNPA2B1 orchestrates immune evasion in colorectal cancer by rewiring tumor-immune cell interactions and suppressing CD8+ T cell infiltration.","authors":"Chuwei Liu, Heng Liang, Peipei Wang, Min Xiao, Yuyan Zheng, Shijia Yan, Yuan Deng, Ruonian Liu, Arabella H Wan, Zhi Wang, Xiongbin Lu, Wu Song, Weiling He, Guohui Wan","doi":"10.1158/2326-6066.CIR-25-0433","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0433","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has transformed colorectal cancers (CRCs) therapy, yet the majority of microsatellite-stable (MSS) CRCs remain refractory due to insufficient tumor-immune cell crosstalk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. Here, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in CRC, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a non-inflamed (\"cold\") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized MSS CRCs to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1'simpact on tumor-immune interactions, and showed that it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in CRC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328238","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":"Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells.","authors":"Ying Luo, Taidou Hu, Chen Yao, Tuoqi Wu","doi":"10.1158/2326-6066.CIR-25-0203","DOIUrl":"10.1158/2326-6066.CIR-25-0203","url":null,"abstract":"<p><p>Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell-fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and T-cell receptor (TCR) profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T-cell activation and exhaustion compared to those recognizing other tumor antigens. In the tumor-draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared to clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph-node residence predicted a poorer response to immune checkpoint inhibitors by cancer patients. In conclusion, we have identified a transcriptional program that controls the cell-fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278986","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}
Shayan C Avanessian, Renske J E van den Bijgaart, Nayvin W Chew, Valentina M Supper, Thao T Tang, Yuzheng Zhang, Ying-Qi Zhao, Kokoro Abe, Jordan Gauthier, Kevin C Barry
{"title":"IL-2/IL-15 signaling induces NK cell production of FLT3LG augmenting anti-PD-1 immunotherapy.","authors":"Shayan C Avanessian, Renske J E van den Bijgaart, Nayvin W Chew, Valentina M Supper, Thao T Tang, Yuzheng Zhang, Ying-Qi Zhao, Kokoro Abe, Jordan Gauthier, Kevin C Barry","doi":"10.1158/2326-6066.CIR-24-1259","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1259","url":null,"abstract":"<p><p>Natural killer (NK) cells play a critical role in anti-cancer immunity through their direct cytotoxicity and production of cytokines, such as Flt3L. NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. Here, we show that NK cell production of Flt3l in the tumor is regulated by activation, and that activation by IL-2 and IL-15 uniquely induced Flt3L expression in NK cells. In melanoma, IL-2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Further, NK cell subsets differentially regulated Flt3L in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL-2-family signaling and upregulated Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279007","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":"CAR-ving a Path: Metalloprotease-Engineered CAR T Cells Tunnel through Solid Tumors.","authors":"Alessandro Gasparetto, Roberto Chiarle","doi":"10.1158/2326-6066.CIR-25-1097","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1097","url":null,"abstract":"<p><p>Overcoming the physical barriers of the tumor microenvironment remains a major obstacle for chimeric antigen receptor (CAR) T-cell therapy in solid tumors. In this issue, Van Pelt and colleagues show that engineering GD2-targeting CAR T cells to express matrix metalloproteinase 7 and osteopontin-b enhances their ability to infiltrate tumors rich in extracellular matrix. These modifications improve functionality in preclinical models without increasing off-target toxicity. The findings highlight a promising strategy to design CAR T cells with extracellular matrix-remodeling capabilities. See related article by Van Pelt et al., p. XX .</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1-OF2"},"PeriodicalIF":8.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249986","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}
Hillary G Pratt, Alyson M Stevens, Michael Sestito, Mercy Ojetunde, Abby D Ivey, Nicole E Mihalik, Kayla J Steinberger, Britney Niemann, E Hannah Hoblitzell, Edwin Wan, Timothy D Eubank, Brian A Boone
{"title":"Neutrophil Extracellular Traps Modulate Recruitment and Immunosuppression of Macrophages in Pancreatic Adenocarcinoma.","authors":"Hillary G Pratt, Alyson M Stevens, Michael Sestito, Mercy Ojetunde, Abby D Ivey, Nicole E Mihalik, Kayla J Steinberger, Britney Niemann, E Hannah Hoblitzell, Edwin Wan, Timothy D Eubank, Brian A Boone","doi":"10.1158/2326-6066.CIR-24-0534","DOIUrl":"10.1158/2326-6066.CIR-24-0534","url":null,"abstract":"<p><p>Pancreatic adenocarcinoma (PDAC) has a dismal survival rate due to limited effective therapies. Although studies have focused on the influence of innate immune cells on adaptive immune cell functions, few have explored interactions between innate immune cells, which modulate the PDAC tumor microenvironment (TME). Macrophages are responsible for the clearance of neutrophil-mediated inflammation in physiologic, resolving immune responses; however, both of these cell types coexist in the TME, suggesting a failure of macrophages to clear neutrophils in PDAC. We sought to determine how neutrophil extracellular traps (NET), neutrophil release of decondensed chromatin, and intracellular contents affect monocyte/macrophage populations in the PDAC TME. Utilizing samples from patients with PDAC, we demonstrated elevated levels of the monocyte chemokine CCL2 in plasma, as well as elevated NET citrullinated histone H3 and the pan-macrophage marker CD68 in the PDAC TME via fluorescent IHC. To determine how NETs affected macrophage populations in the PDAC TME, we targeted NETs with DNase I treatment to digest extracellular DNA released from NETs or with genetic knockout of PAD4, an enzyme required for NET formation. NET depletion resulted in an elevation in the pan-macrophage marker F4/80. The depletion led to an increased T-cell stimulatory signal, CD80, whereas the protumor macrophage marker CD206 was decreased. We further demonstrated that macrophages in the NET-deficient PDAC TME may be recruited through the CCL2/CCR2 axis, and CCL2 was released from tumor cells and macrophages in the presence of IFNγ. Taken together, our findings reveal that inhibition of NETs can prime the innate immune response toward an antitumor phenotype.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1547-1560"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752499","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":"Spatial Analysis of the Tumor Microenvironment in Diffuse Large B-cell Lymphoma Reveals Clinically Relevant Cell Interactions and Recurrent Cellular Neighborhoods.","authors":"Matias Autio, Suvi-Katri Leivonen, Leo Meriranta, Marja-Liisa Karjalainen-Lindsberg, Teijo Pellinen, Sirpa Leppä","doi":"10.1158/2326-6066.CIR-24-1163","DOIUrl":"10.1158/2326-6066.CIR-24-1163","url":null,"abstract":"<p><p>Recent studies have explored the composition of the tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL) However, cell-to-cell interactions, along with the spatial organization of DLBCL TME and their impact on patient outcomes, have remained poorly characterized. We applied multiplex immunofluorescence, cell phenotyping, and neighborhood analysis to investigate 1,218,756 single cells in 99 samples from patients with primary DLBCL. We identified 17 cell phenotypes and 10 recurrent cellular neighborhoods (RCN) across samples, subdividing DLBCLs into immune-poor areas and areas with diverse immune cell infiltrates. Avoidance of B cells and PD-1+ T cells was associated with less aggressive clinical characteristics and favorable survival. Likewise, the proximity of CD8+ T cell-rich and immune-poor RCNs translated to favorable patient outcomes, and the proximity of PD-L1+ B cell-rich and CD8+ T cell-rich RCNs to unfavorable patient outcomes. Our findings provide insights into the spatial interactions and organization of DLBCL TME with implications for patient outcomes.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1674-1686"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793563","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}
Haidong Dong, Hyoungjun Ham, Whitney Barham, Ti Wen, Jacob B Hirdler, Zhiming Mao, Dallin S Ashton, Wenjing Zhang, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau
{"title":"A Dual Role for NKG7 in T-cell Cytotoxicity and Longevity.","authors":"Haidong Dong, Hyoungjun Ham, Whitney Barham, Ti Wen, Jacob B Hirdler, Zhiming Mao, Dallin S Ashton, Wenjing Zhang, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau","doi":"10.1158/2326-6066.CIR-25-0384","DOIUrl":"10.1158/2326-6066.CIR-25-0384","url":null,"abstract":"<p><p>The effectiveness of T cell-based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell-based immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1510-1515"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871623","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}
Eléonore Weber-Delacroix, Marylou Panouillot, Marie Laviron, François Lanthiez, Tristan Philippe, Sandrine Barthélémy, Solène Fastenackels, Armanda Casrouge, Benoit L Salomon, Ingrid Sassoon, Jeremy Baudhuin, Ilaria Onorati, Marianne Kambouchner, Nahla Cucherousset, Christophe Combadière, Boris Duchemann, Marie-Caroline Dieu-Nosjean, Alexandre Boissonnas
{"title":"Regulatory T Cells Poise the Myeloid Landscape after Chemotherapy in Lung Tumors.","authors":"Eléonore Weber-Delacroix, Marylou Panouillot, Marie Laviron, François Lanthiez, Tristan Philippe, Sandrine Barthélémy, Solène Fastenackels, Armanda Casrouge, Benoit L Salomon, Ingrid Sassoon, Jeremy Baudhuin, Ilaria Onorati, Marianne Kambouchner, Nahla Cucherousset, Christophe Combadière, Boris Duchemann, Marie-Caroline Dieu-Nosjean, Alexandre Boissonnas","doi":"10.1158/2326-6066.CIR-25-0103","DOIUrl":"10.1158/2326-6066.CIR-25-0103","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) and regulatory T cells (Treg) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. Although Tregs are well known for their immunosuppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. In this study, we have shown that in human and mouse lung cancer, chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward not only a proinflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the proinflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the proinflammatory signature of the MPs, and improved survival in the mouse model. Targeting the cross-talk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1561-1575"},"PeriodicalIF":8.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552395","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}