Peptidoglycan‐treated tumor antigen‐pulsed dendritic cells impart complete resistance against tumor rechallenge. (26th June 2020)

• Record Type: Journal Article
• Authors: Patidar, A.; Selvaraj, S.; Chauhan, P.; Guzman, C. A.; Ebensen, T.; Sarkar, A.; Chattopadhyay, D.; Saha, B.
• Is Part Of: Clinical and experimental immunology. Volume 201:Number 3(2020)
• Page Start: 279
• Page End: 288
• Publication Date: 2020-06-26
• Subjects: anti‐tumor vaccine -- cytokines -- cytotoxic T cells -- dendritic cells -- peptidoglycan -- Toll‐like receptors; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.13468
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: Solid tumors elicit suppressive T cell responses which impair antigen‐presenting cell (APC) functions. Such immune suppression results in uncontrolled tumor growth and mortality. Addressing APC dysfunction, dendritic cell (DC)‐mediated anti‐tumor vaccination was extensively investigated in both mice and humans. These studies never achieved full resistance to tumor relapse. Herein, we describe a repetitive RM‐1 murine tumor rechallenge model for recurrence in humans. Using this newly developed model, we show that priming with tumor antigen‐pulsed, Toll‐like receptor (TLR)2 ligand‐activated DCs elicits a host‐protective anti‐tumor immune response in C57BL/6 mice. Upon stimulation with the TLR2 ligand peptidoglycan (PGN), the tumor antigen‐pulsed DCs induce complete resistance to repetitive tumor challenges. Intra‐tumoral injection of PGN reduces tumor growth. The tumor resistance is accompanied by increased expression of interleukin (IL)‐27, T‐box transcription factor TBX21 (T‐bet), IL‐12, tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ, along with heightened cytotoxic T lymphocyte (CTL) functions. Mice primed four times with PGN‐stimulated tumor antigen‐pulsed DCs remain entirely resistant to repeat challenges with RM‐1 tumor cells, suggesting complete prevention of relapse and recurrence of tumor. Adoptive transfer of T cells from these mice, which were fully protected from RM‐1 rechallenge, confers anti‐tumor immunity to syngeneic naive recipient mice upon RM‐1 challenge. These observations indicate that PGN‐activated DCs induce robust host‐protective anti‐tumor T cells that completely resist tumor growth and recurrence. Abstract : To address APC dysfunction in various tumor malignancies and recurrence, we repetitively challenged mice with RM‐1 tumor cells after immunization with PGN‐activated tumor antigens‐pulsed DCs. The study reveals that twice or four times administration of such DC formulation enhance host‐survival by inducing host‐protective, adoptively transferable, robust anti‐tumor T cells. The mice also remain resistant to tumor rechallenge, instilling a protocol that removes a major bottleneck in anti‐tumor immunotherapy impeding the relapse and tumorigenesis.