ABSTRACT: Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.
Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)
The Dendritic Cell-based Vaccine PROTEXI leverages Antiviral CD4 T cell Memory to boost anti-tumor immune responses in mice
(1) Kang JM (2) Han EH (3) Choi JK (4) Youm S (5) Pareek T (6) Levi L (7) Kim SJ (8) Letterio J (9) Lim S
(1) Kang JM (2) Han EH (3) Choi JK (4) Youm S (5) Pareek T (6) Levi L (7) Kim SJ (8) Letterio J (9) Lim S
Author Info: (1) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. Department of Pediatric Hematology &

Author Info: (1) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (2) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (3) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (4) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (5) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (6) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (7) MedPacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, Republic of Korea. (8) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. John.Letterio@UHHospitals.org. The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. John.Letterio@UHHospitals.org. (9) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. SeunghwanLim@Celloram.com. Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. SeunghwanLim@Celloram.com.

Citation: Nat Commun 2026 Jul 27 17: Epub07/27/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42509244
Tumor-induced dendritic cell deregulation perturbs T cell proliferation and predicts clinical outcome in acute lymphoblastic leukemia
(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S
(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S
Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hop

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (3) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (4) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (5) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (6) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (7) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (8) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (9) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (10) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (11) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (12) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (13) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; The Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (14) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (15) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (16) Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. (17) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (19) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (20) Department of Clinical Population and Public Health Sciences, University of Southern California, Los Angeles, CA 91016, USA. (21) Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (22) Schneider Children's Medical Center, Tel Aviv University, Felsenstein Research Institute, Tel Aviv, Israel. (23) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (24) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (25) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: sswaminathan@coh.org.

Citation: Cell Rep Med 2026 Jul 28 102945 Epub07/28/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42520804
CCR7+ activated dendritic cells are essential for spontaneous and immunotherapy-driven anti-tumor immunity
(1) Koufaki MA (2) Richardson E (3) Bonavita E (4) Reeves R (5) Moeini A (6) Chiang SC (7) Banyard A (8) Russo M (9) Earnshaw CH (10) Bell CR (11) Flanagan E (12) Pelly VS (13) Nebot-Bral L (14) Pidoux A (15) Dunn P (16) Sahoo S (17) Henri S (18) Malissen B (19) MacDonald AS (20) Moncaut N (21) Zelenay S
(1) Koufaki MA (2) Richardson E (3) Bonavita E (4) Reeves R (5) Moeini A (6) Chiang SC (7) Banyard A (8) Russo M (9) Earnshaw CH (10) Bell CR (11) Flanagan E (12) Pelly VS (13) Nebot-Bral L (14) Pidoux A (15) Dunn P (16) Sahoo S (17) Henri S (18) Malissen B (19) MacDonald AS (20) Moncaut N (21) Zelenay S
Author Info: (1) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (2) Cancer Inflammation and Immunity, Cancer Research U

Author Info: (1) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (2) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (3) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (4) Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (5) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (6) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (7) Flow Cytometry, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (8) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (9) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; Dermatology Centre, Northern Care Alliance NHS Foundation Trust & Division of Musculoskeletal and Dermatological Sciences, Manchester NIHR Biomedical Research Centre, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. (10) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (11) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (12) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (13) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (14) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (15) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (16) Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (17) Centre d'Etude des Pathologies Respiratoires, INSERM, UMR 1100, Universit de Tours, Tours, France. (18) Centre d'Immunologie de Marseille-Luminy, INSERM, CNRS, Aix Marseille Universit, Marseille, France; Centre d'Immunophnomique, INSERM, CNRS, PHENOMIN, Celphedia, Aix Marseille Universit, Marseille, France. (19) Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK. (20) Genome Editing and Mouse Models, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (21) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK. Electronic address: santiago.zelenay@cruk.manchester.ac.uk.

Citation: Immunity 2026 Aug 4 Epub08/04/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42551427
Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer
(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M
(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M
Author Info: (1) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) MD Anderson Epigenomics Therapy Initiative, Department of Genomic

Author Info: (1) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Otolaryngology-Head and Neck Surgery, Gleiberman Head and Neck Cancer Center, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (6) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (8) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fonetto@mdanderson.org. (10) Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: pnagarajan@mdanderson.org. (11) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. (12) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (15) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (16) Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel. (17) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (22) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (23) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (24) Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mrmigden@mdanderson.org. (25) Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (28) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. Electronic address: mcgraid@ccf.org. (29) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: krai@mdanderson.org. (33) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Cancer Neuroscience Program, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mamit@mdanderson.org.

Citation: Cell 2026 Aug 5 Epub08/05/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42556334
Dendritic cell circadian clocks shape memory CD8+ T cell differentiation
(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R
(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R
Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Alb

Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (4) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (5) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (6) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (7) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (8) Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands. (9) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Citation: Sci Adv 2026 Jul 31 12:eaeh3719 Epub07/31/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42536728
Tags:
First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts
(1) Haldar SD (2) Huff AL (3) Wang HH (4) Zhu Z (5) Berg M (6) Lu J (7) Sun N (8) Abou Diwan E (9) Sinan H (10) Thoburn CJ (11) Guo MZ (12) Yoshida T (13) Chu LC (14) Ferguson AK (15) Sidiropoulos DN (16) Kagohara LT (17) Ho WJ (18) Bever KM (19) Baretti M (20) Yarchoan M (21) Laheru DA (22) Nauroth JM (23) Thomas AM (24) Wang H (25) Azad NS (26) Goggins MG (27) Jaffee EM (28) Zaidi N
(1) Haldar SD (2) Huff AL (3) Wang HH (4) Zhu Z (5) Berg M (6) Lu J (7) Sun N (8) Abou Diwan E (9) Sinan H (10) Thoburn CJ (11) Guo MZ (12) Yoshida T (13) Chu LC (14) Ferguson AK (15) Sidiropoulos DN (16) Kagohara LT (17) Ho WJ (18) Bever KM (19) Baretti M (20) Yarchoan M (21) Laheru DA (22) Nauroth JM (23) Thomas AM (24) Wang H (25) Azad NS (26) Goggins MG (27) Jaffee EM (28) Zaidi N
Author Info: (1) The University of Texas MD Anderson Cancer Center Houston, TX United States. ROR: https://ror.org/04twxam07 (2) Johns Hopkins Medicine Baltimore United States. ROR: https://ror

Author Info: (1) The University of Texas MD Anderson Cancer Center Houston, TX United States. ROR: https://ror.org/04twxam07 (2) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (3) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (4) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (5) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (6) Johns Hopkins University United States. ROR: https://ror.org/00za53h95 (7) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (8) Johns Hopkins School of Medicine Baltimore, MD United States. (9) Icahn School of Medicine at Mount Sinai New York United States. ROR: https://ror.org/04a9tmd77 (10) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (11) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (12) The Johns Hopkins Medical Institutions Baltimore, MD United States. (13) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (14) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (15) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (16) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (17) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (18) Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland United States. ROR: https://ror.org/05m5b8x20 (19) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (20) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (21) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. ROR: https://ror.org/05m5b8x20 (22) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (23) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (24) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (25) Johns Hopkins University Baltimore, Maryland United States. ROR: https://ror.org/00za53h95 (26) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (27) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (28) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354

Citation: Cancer Discov 2026 Jul 16 Epub07/16/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42458705
CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells Featured
(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD
Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.
(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD
Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.
ABSTRACT: It is well established that CD4⁺ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8⁺ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4⁺ T cells are essential not only during T-cell priming, but also to maintain T-cell effector function within the tumor. Depleting CD4⁺ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8⁺ T cells and their intratumoral accumulation. CD4⁺ T cells were required for functional reinvigoration of CD8⁺ tumor-infiltrating lymphocytes (TIL) by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4⁺ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming, but rather depended on IL-2 and IFNγ. Using a TCR-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Aᵇ complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4⁺ T-cell help after priming. These findings reveal temporally distinct requirements for CD4⁺ T-cell help and establish a need for continuous CD4⁺/CD8⁺ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.
Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://

Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (3) Washington University in St Louis St Louis United States. (4) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (5) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (6) Washington University in St. Louis United States. ROR: https://ror.org/01yc7t268 (7) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (8) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (9) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (10) Washington University in St. Louis Saint Louis, MO United States. ROR: https://ror.org/01yc7t268 (11) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (12) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (13) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (14) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (15) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (16) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268

Citation: Cancer Immunol Res 2026 Jul 16 Epub07/16/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462143
Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma Spotlight
(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) Mul JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S
Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.
Contributed by Shishir Pant
(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) Mul JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S
Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.
Contributed by Shishir Pant
Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School

Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: lilit.karapetyan@moffitt.org. (2) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (3) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (8) Department of Molecular Biosciences, University of South Florida, Tampa, FL 33612, USA. (9) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (10) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (11) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (12) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (13) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (14) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (15) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (16) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (17) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (18) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (19) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (20) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (21) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (22) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (23) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (24) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (25) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (26) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (27) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (28) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (29) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (30) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (31) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (32) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (33) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: amod.sarnaik@moffitt.org. (34) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: matthew.beatty@moffitt.org. (35) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: shari.pilon-thomas@moffitt.org.

Citation: Med 2026 Jul 29 101231 Epub07/29/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42526429
Tumor-specific antibodies elicited by engineered bacteria promote bladder cancer immunotherapy in preclinical mouse models Spotlight
(1) Rouanne M (2) Chen N (3) Mariuzza DL (4) Yang Z (5) Li F (6) de Los Santos-Alexis K (7) Savage TM (8) Vincent RL (9) Mendelsohn CL (10) Danino T (11) Arpaia N
Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.
Contributed by Paula Hochman
(1) Rouanne M (2) Chen N (3) Mariuzza DL (4) Yang Z (5) Li F (6) de Los Santos-Alexis K (7) Savage TM (8) Vincent RL (9) Mendelsohn CL (10) Danino T (11) Arpaia N
Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.
Contributed by Paula Hochman
ABSTRACT: The intratumoral microbiome has recently emerged as a potential hallmark of cancer, with implications for response or resistance to therapy. Bacteria can either promote or inhibit cancer growth. However, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment. Here, we engineered the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to express the human chemokine CXCL13 (C-X-C motif chemokine ligand 13), a critical component of germinal center (GC) formation. Antibody affinity maturation and class switching are fundamental aspects of adaptive immune response. Both occur primarily in the GCs of secondary lymphoid organs for defense against pathogens. Immune checkpoint blockade (ICB) efficacy is primarily driven by T cells; however, recent studies in mice and humans have shown that humoral immune responses act as critical partners for ICB-mediated antitumor activity. Using orthotopic models of bladder cancer, intravesically delivered engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor-draining lymph nodes after intravesical delivery. When combined with programmed cell death protein 1 (PD-1) blockade, engineered EcN improved antitumor activity in two aggressive, fast-growing, and immunologically cold orthotopic mouse models of bladder cancer. Mechanistically, this antitumor effect was dependent on the presence of CD8(+) T cells and CD4(+) T follicular helper cells; combination therapy increased tumor-specific antibody responses and promoted long-term survival and protective immunity upon tumor rechallenge. Thus, we demonstrate that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.
Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (2) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (3) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (4) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (5) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (6) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (7) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (9) Department of Urology, Columbia University, New York, NY 10032, USA. (10) Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Data Science Institute, Columbia University, New York, NY 10027, USA. (11) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Citation: Sci Transl Med 2026 Jul 22 18:eadv7600 Epub07/22/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42485436
