Blockade of Programmed Death Ligand 1 Enhances the Therapeutic Efficacy of Combination Immunotherapy against Melanoma

Abstract

Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1. PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DCs) and B16 melanoma. In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-γ production and cytotoxicity by Ag-specific T cells. In vivo, the systemic administration of anti–PD-L1 Ab plus melanoma peptide-pulsed DCs resulted in a higher number of melanoma peptide-specific CD8+ T cells, but this combination was insufficient to delay the growth of established B16 melanoma. Although the addition of 600 rad of total body irradiation delayed tumor growth, further adoptive transfer of Ag-specific CD8+ T cells was needed to achieve tumor regression and long-term survival of the treated mice. Lymphopenic mice treated with anti–PD-L1 Ab demonstrated increased activation and persistence of adoptively transferred T cells, including a higher number of CD8+ T cells infiltrating the tumor mass. Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma.

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

“…On the basis of these considerations, preliminary results in mice models suggest that combination therapies may be helpful in restoring an activating phenotype in the tumor microenvironment [71]. In experimental models combining B7-H1/PD-1 blockade with cancer vaccines [72][73][74][75], adoptive transfer of preactivated T cells, or T cell stimulation with anti-CD137 [76] often provides dramatic synergistic antitumor effects, in some cases eradicating well-established tumors.…”

Efficient Treg depletion induces T‐cell infiltration and rejection of large tumors

“…Usually an effect on tumor growth has been observed only in prophylactic settings when Treg were depleted before or no later than 2 days after tumor inoculation, whereas PC-61-mediated Treg depletion in animals carrying established tumors had generally no or only little effect on tumor growth [25][26][27][28]. Significant therapeutic success was only observed when complex combinatorial approaches were applied such as total body irradiation combined with adoptive T-cell transfer and vaccination [29], and additional treatment with anti-PDL1 antibody [30], but usually mice were treated when tumors were still small (3-4 days after s.c. tumor inoculation). Thus, immunotherapy of large established tumors remains a major challenge.…”

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

“…PD-L1/PD-1 interaction is therefore used by several tumours to avert the cytotoxic attack of effector T cells [53][54][55][56][57][58]. Thus, its blockade augments anti-cancer immune responses and improves immunotherapy [59,60]. However, in many instances PD-L1/PD-1 blockade or silencing using siRNA results in limited therapeutic activities, unless given in combination with other treatments such as co-administration with anti-CTLA4 antibodies [61,62], PD-L2-blocking antibodies [63], TLR ligands [62], chemotherapy [64], cytokine treatments [65] or modulators of intracellular signalling pathways in DCs [39].…”

“…Hyperactivated T cells exhibit a higher proliferation rate, increased cytokine production, and possibly differentiation of multifunctional T cells [32,37,39,60,66]. Particularly the capacity of PD-L1/PD-1 blockade to stimulate polyfunctional T cells has important therapeutic implications [67][68][69].…”