CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Abstract

In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2 D4) was found to enhance IFN-γ-producing-CD8 + T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2 D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2 D4 and antitumor immunity, as evidenced by the reversal of tumor-infiltrating CD8 + T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.

The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

“…Doxorubicin pretreatment, followed by FAP/survivin DNA vaccine, reduces 4T1 TNBC cell growth by eliminating MDSCs [ 128 ]. These observations are consistent with other in situ, B-cell based, and other vaccine strategies that eliminate MDSCS [ 129 , 130 , 131 ]. Additional work is required to interrogate the role of MDSCs in vaccine success and test MDSC-targeting adjuvants in BC vaccine clinical trials.…”

Identification of cluster of differentiation molecule-associated microRNAs as potential therapeutic targets for gastrointestinal cancer immunotherapy

“…The immune function of miR-200a and CD86 in GI cancer needs further investigation. CD160 is one of the inhibitory receptors on T cells, 35 which exhibits an immunosuppressive effect in the tumor microenvironment. Negative regulation of CD160 might activate the immune response of T cells, thereby increasing the efficacy of cancer immunotherapy.…”

Unlocking PD‐1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression

“…In parallel, a control group received intravenous injections of Armenian hamster IgG (200 μg per mouse, BioXCell). Tumour dimensions were meticulously measured twice a week, and the corresponding tumour volumes were computed using the formula: V = 0.5 × D × d 2 , where ‘D’ stands for the longitudinal diameter and ‘d’ for the latitudinal diameter 27 . When tumours reached a diameter of 15 mm, mice were humanely euthanized through CO 2 exposure, as stipulated by the Animal Care and Use Committee Guidelines of Xi'an Jiaotong University (2018‐306).…”

“…where 'D' stands for the longitudinal diameter and 'd' for the latitudinal diameter. 27 When tumours reached a diameter of 15 mm, mice were humanely euthanized through CO 2 exposure, as stipulated by the Animal Care and Use Committee Guidelines of Xi'an Jiaotong University (2018-306). The survival duration of these tumour-bearing mice was then ascertained.…”