Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

Abstract

Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies.

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

“…In this study, we show greater antitumor effects when combining pathogenbased cancer vaccine with ACT of dual-specific CD8 T cells than recombinant Listeria expressing a tumor antigen. This result can be explained by a greater magnitude of clonal expansion of adoptively transferred tumor-specific CD8 T cells than that from endogenous T cells, which supports the idea that the initial T-cell-mediated killing crucially depends on sufficiently high doses of T cells within the tumor for successful eradication (26).…”

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…Unfortunately, current preclinical animal models do not allow us to study this possibility in the context of adoptive Tcell transfer. Many previous studies combining virotherapy and ACT have focused on oncolytic viruses encoding TAAs, thus relying mostly on oncolysis and vaccination effect against a particular tumor epitope (8,(41)(42)(43). In our hands, the mere adenoviral backbone acted as an adjuvant and boosted the endogenous antitumor immunity elicited by ACT.…”

“…Peripheral tolerance of tumor-specific T cells due to insufficient costimulation by professional antigen-presenting cells (APC) may result in T-cell deletion or anergy (7). Furthermore, the highly immunosuppressive TME typically renders infiltrating T cells incapable of killing their target (tumor) cells (8). For successful cancer immunotherapy, the TME has to be immunogenic enough in order to accomplish T-cell-mediated cytolysis and subsequent antitumor responses.…”

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

“…Their accumulation and suppression activity were caused by IFNg produced by the effector CTLs (40). Similarly, a recent report showed that the low efficacy of vaccination in melanoma-bearing mice was associated with IFNg production by early attacking and invading CD8 þ T cells, resulting in the upregulation of immunosuppressive processes that suppressed local Tcell activation (41). In our ex vivo system, we showed that IFNg production by activated CD4 þ T cells was required to sustain the initial activation of M-MDSCs and render functional the M-MDSC:mast cell-suppressive axis.…”