Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment

Arwa Ali; Menghan Gao; Alexandros Iskantar; Hai Wang; Alex Karlsson-Parra; Di Yu; Chuan Jin

doi:10.3389/fimmu.2023.1146413

Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment

Front Immunol. 2023 Aug 15:14:1146413. doi: 10.3389/fimmu.2023.1146413. eCollection 2023.

Authors

Arwa Ali¹, Menghan Gao¹, Alexandros Iskantar¹, Hai Wang^{2

3}, Alex Karlsson-Parra⁴, Di Yu¹, Chuan Jin¹

Affiliations

¹ Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
² Chinese Academy of Science (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ Mendus AB, Stockholm, Sweden.

Abstract

As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ⁺ CD8⁺ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T_RM) CD8⁺ T cells (CD103⁺CD49a⁺CD69⁺). The combination treatment also led to increased infiltration of CD39⁺CD103⁺ tumor-specific CD8⁺ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

Keywords: allogeneic dendritic cells; ilixadencel; tissue-resident CD8+ T-cells; tumor-reactive CD8+ T-cells; tumor-specific CD8+ T-cells; α4-1BB therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic
Administration, Cutaneous
Animals
CD8-Positive T-Lymphocytes*
Dendritic Cells
Hematopoietic Stem Cell Transplantation*
Killer Cells, Natural
Mice

Substances

Adjuvants, Immunologic

Grants and funding

The Swedish Cancer Society [222229Pj], the Swedish Childhood Cancer Fund [PR2022-0105], the Göran Gustafsson’s foundation [Di Yu], the Erik, Karin and Gösta Selanders foundation [Chuan Jin], and Mendus AB supported this study.