Integrin β4–Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis

Abstract

Integrin b4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/ anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumordraining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4targeted immunotherapy reduced not only the number of ITGB4 high CSCs in residual 4T1 and SCC7 tumors but also their tumorinitiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy. Significance: Immune targeting of ITGB4 may represent a novel approach to improve the efficacy of current cancer immunotherapies.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study

“…Furthermore, the prophylactic use of granulocyte-colony stimulating factor in Japanese patients was approved in 2014; therefore, the higher incidence of febrile neutropenia in this study is not thought to be a significant concern in practice. In support of this, in the phase III randomized PEONY trial of Asian patients with early/locally advanced HER2 breast cancer treated with pertuzumab plus trastuzumab and docetaxel, concomitant use of prophylactic granulocyte-colony stimulating factor was permitted, with only four patients (1.8%) reported to develop febrile neutropenia [ 19 ]. Similar to the results observed in our study, a subgroup analysis of Asian patients in CLEOPATRA demonstrated a higher incidence of febrile neutropenia in Asian patients than in patients from other regions [ 20 ].…”

Cancer stem cell antigens as targets for new combined anti-cancer therapies

“…For example, one DC-based vaccine targets integrin β4, which is overexpressed in breast and colon cancers and plays a role in CSC self-renewal. The humoral and cellular immune responses elicited by this vaccine are effective in inhibiting tumor growth and spontaneous pulmonary metastases as they kill both CSCs and differentiated cancer cells (52).…”

“…The results obtained from the MUC1-vaccine trials suggest that, like all monotherapies, single immunotherapy is insufficient for cancer treatment, and that combinatorial approaches are needed (Figure 1). Several studies on preclinical models of melanoma, breast, colon and head and neck squamous cell carcinomas (HNSCC) have shown that combining CSC-targeting vaccines with ICIs induces increased activation of tumor-specific CD8 + T cells, decreased CSC frequency and better tumor-progression control than single treatments, paving the way for clinical experimentation (33,52,63,64).…”

Comprehensive Analysis of the Prognostic Value of ITGB Superfamily Members in Gastric Cancer Using Bioinformatics Analysis

“…It has been reported that ITGB3dependent uptake of extracellular vesicles, for which focal adhesion kinase is required as a key role, could promote the metastasis of breast cancer cells [34]. ITGB4 and ITGB6 targeted immunotherapy is a promising strategy, showing a great effect on the inhibition of the progression and metastasis of tumors [35,36]. Studies have also suggested that ITGB7 and ITGB8 have the potential to mediate the progression of tumors, paving the way for a novel therapeutic approach for the treatment for cancers [37][38][39].…”