Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.
Contributed by Shishir Pant
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8(+) T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8(+) T cells or tumor cell MHC expression but instead requires IFN_-producing CD4(+) T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4(+) T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4(+) T cell-IFN_ axis could be efficacious in PDAC.
Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farbe
Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (2) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School Program in Virology, Boston, MA, USA. (3) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (6) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (7) Brookline High School, Brookline, MA, USA. (8) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (9) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (10) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (11) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (12) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (13) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (14) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (16) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (17) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (18) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (20) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (21) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (22) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, MA, USA. (24) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (27) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (28) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (30) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (31) Bristol Myers Squibb, Princeton, NJ, USA. (32) Bristol Myers Squibb, Princeton, NJ, USA. (33) Bristol Myers Squibb, Princeton, NJ, USA. (34) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (35) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (36) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.
