Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines

Abstract

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to T H2 -like signature and immunosuppressive regulatory T (T REG ) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

“…For example, 3 out of 146 patients with solid tumours receiving BLZ945 showed partial response [ 146 ]. Furthermore, additional analysis of peripheral blood monocytes did not show any changes after treatment [ 147 , 148 ].…”

Dendritic Cell Vaccines: A Promising Approach in the Fight against Ovarian Cancer

“…In another study further evaluating the potential prognostic markers for moDC vaccine response, the presence of Tregs in the blood was found to be a negative prognostic factor in OC patients. Indeed, only in patients with a low number of Tregs did the CD8 + T cells increase after moDC vaccination [ 98 ]. In addition, patients that had received moDC vaccination (both Arms 1 and 2) also showed the presence of antigen-specific cytotoxic T cells in the blood [ 97 ].…”

Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

“…In addition, current designs of therapeutic algorithms also rely on combinations of DC-based cancer vaccines with other therapeutic modalities [ 151 , 152 ]. There is also a developing new field that attempts to identify new biomarkers that could predict the therapeutic efficacy of the vaccines based on the patient’s immunotype [ 153 ].…”

“…Despite many disappointments in clinical trials, the use of these cells still showed a notable therapeutic efficacy, and their role in cancer immunotherapy is indeed still ongoing [ 146 , 154 , 155 ]. As research into immunotherapy accelerated after the immune checkpoint inhibitor had entered the field, the efficacy of DC-based immunotherapy was found to be largely restricted by the settings (immunotype) of the patient’s tumor immune microenvironment [ 153 , 156 ]. Moreover, there is growing evidence that the functional heterogeneity of DC populations is even more complex than previously thought [ 73 ], and, therefore, more attention needs to be paid to the way DCs are ex vivo produced for ACT [ 82 ].…”