PD-1 and Tim-3 Regulate the Expansion of Tumor Antigen–Specific CD8+ T Cells Induced by Melanoma Vaccines

Abstract

Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8+ T cells with regard to the inhibitory T cell co-receptors PD-1 and Tim-3 in metastatic melanoma patients who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant (IFA), CpG oligodeoxynucleotide (CpG) and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T-cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in advanced melanoma patients.

Blocking monoclonal antibodies of TIM proteins as orchestrators of anti-tumor immune response

“…62 Additionally, TIM-3 is highly expressed on effector immune cells such as T cells and NK cells, and serves as an exhaustion marker for T cells and NK cells. 45,46,53 Together, these results suggest that the manipulation of TIMs functions by mAbs is a promising and powerful strategy to initiate or amplify an existing immune response against tumors (Fig. 2).…”

“…TIM-3 interacts with galectin-9 and causes exhaustion and apoptosis of antigenspecific CTLs, which correlates with impaired antitumor immune responses. 45,46 TIM-3 expression was also observed on Foxp3 C regulatory T cells; however, the function of TIM-3 in this population should be explored in future studies. 47 Several blocking mAbs have been generated to target mouse and human TIM-3 ( Table 2).…”

“…2E2 and AF2365 clones were effective to enhance proliferation and cytotoxic activities of NK cells, and to expand antigen-specific CD8 C T cells with increased IFN-g production when combined with peptide vaccination of melanoma. 45,46,53 ATIK2a clone, another mAb that targets human TIM-3, was found to induce antibody-dependent cell-mediated cytotoxicity (ADCC), and was effective in eradicating TIM-3-expressing leukemia stem cells in an acute myeloid leukemia model. 54,55 On the other hand, 334823 and 344801 clones may act as antagonist mAb because the cross-linking of these mAb with its targets on NK cells has suppressed NK cell-mediated cytotoxicity in in vitro experiments.…”

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma

“…85 Vaccination results in upregulation of immune checkpoint receptors (e.g., PD1 receptor and T-cell membrane protein 3 (TIM3) that suppresses Th1 cell activation) and induction of Tcell anergy. 86 Studies are being conducted on immune checkpoint inhibitors combined with anti-angiogenic agents or DCbased vaccines in mRCC. Synergy between an anti-PD-L1 antibody and a vaccine against human papillomavirus was shown.…”

Melanoma checkpoint inhibitors

“…A team of U.S. researchers has found that combining a cocktail of antibodies targeting checkpoint proteins with peptide-based cancer vaccines induced a potent and tumor-specific T cell response to treat melanoma. 1 Researchers on the paper founded cancer immunology company CoStim Pharmaceuticals Inc. in 2011. The company is developing combinations of undisclosed checkpoint inhibitors.…”