Abstract
Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies.
Highlights
According to the cancer-immunity cycle, dendritic cells (DCs) play a fundamental role in setting off an anti-tumor specific immune response [1]
In 11 out of the 16 cases indagated the sites of tumor biopsies taken before and after vaccination were of the same type, i.e., soft tissue/nodal or visceral, according to the classification provided in Bartlett et al [27], avoiding any statistically significant imbalance in the level of CD8 expression in the selected pre-treatment sample cohorts
We found that this up-regulation was stronger in the naïve/CT/room temperature (RT) cohort (n = 9, mean ± SEM 3.056 ± 1.268 vs. 13.74 ± 3.242 PDL1% in pre-treatment and post-treatment biopsies, respectively; p = 0.0078), while it did not reach statistically significance in the immune_treated one (n = 5, mean ± SEM 4,920 ± 3,068 vs. 4,295 ± 1,653 PDL1% in pretreatment and post-treatment biopsies, respectively; p = 0.6250), suggesting a positive correlation with the observed higher density of intratumoral CD8+ T cell infiltrate (Figure 2D)
Summary
According to the cancer-immunity cycle, dendritic cells (DCs) play a fundamental role in setting off an anti-tumor specific immune response [1]. Under ideal circumstances, DCs take up tumor antigens and promote the generation of antitumor specific T cells, which infiltrate the tumor bed and kill their target cells through cytolytic mechanisms (i.e., perforin and granzyme B) The translation of this concept into the clinic has led to the design of DC-based therapeutic vaccines [2]. Evidence available from the literature has been primarily obtained in patients treated with immune checkpoint inhibitors [14, 15], and aimed at identifying biomarkers predictive of response to therapy and finding potentially actionable synergistic targets for improving their clinical efficacy In this line, clinical experience with combined anti-CTLA4 and anti-PD1 immunomodulating antibodies has shown better efficacy in melanoma patients, but at the expenses of more severe treatment-related toxicities. Our findings support the use of DC immunotherapy as a TME modulating therapeutic tool, which might broaden the effectiveness of anti-PD1/PDL1 therapies
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