Blocking LAIR1 signaling in immune cells inhibits tumor development

Abstract

The current immune checkpoint blockade therapy has been successful in treating some cancers but not others. New molecular targets and therapeutic approaches of cancer immunology need to be identified. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) is an immune inhibitory receptor expressing on most immune cell types. However, it remains a question whether we can specifically and actively block LAIR1 signaling to activate immune responses for cancer treatment. Here we report the development of specific antagonistic anti-LAIR1 monoclonal antibodies and studied the effects of LAIR1 blockade on the anti-tumor immune functions. The anti-LAIR1 antagonistic antibody stimulated the activities of T cells, natural killer cells, macrophages, and dendritic cells in vitro. The single-cell RNA sequencing analysis of intratumoral immune cells in syngeneic human LAIR1 transgenic mice treated with control or anti-LAIR1 antagonist antibodies indicates that LAIR1 signaling blockade increased the numbers of CD4 memory T cells and inflammatory macrophages, but decreased those of pro-tumor macrophages, regulatory T cells, and plasmacytoid dendritic cells. Importantly, the LAIR1 blockade by the antagonistic antibody inhibited the activity of immunosuppressive myeloid cells and reactivated T cells from cancer patients in vitro and impeded tumor metastasis in a humanized mouse model. Blocking LAIR1 signaling in immune cells represents a promising strategy for development of anti-cancer immunotherapy.

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer

“…In a retrospective study, LAIR1 expression was found to associate to poor prognosis in invasive breast carcinoma ( 177 ), but also to resistance to PD1/PD-L1 inhibition in patients ( 178 ). Of interest, LAIR1 blockade by antagonist antibodies inhibited tumor development in a humanized mouse model by affecting, among others, the recruitment of pro-tumorigenic pDCs ( 179 ). In addition to blocking antibody, LAIR1-inhibitory signaling can be blocked also by taking advantage of LAIR2, a natural agonist ( 180 ) as proposed by a work using a dimeric LAIR2 Fc fusion protein to target collagens in tumors and reverse immune suppression ( 181 ).…”

“…In addition to blocking antibody, LAIR1-inhibitory signaling can be blocked also by taking advantage of LAIR2, a natural agonist ( 180 ) as proposed by a work using a dimeric LAIR2 Fc fusion protein to target collagens in tumors and reverse immune suppression ( 181 ). The potential of LAIR1 blockade in cancer immunotherapy is currently emerging ( 179 , 182 ). However, since LAIR1 is widely expressed also by tumor cells, where it may induce either proliferation or inhibition depending on the tumor type ( 173 ), its therapeutic exploitation needs to be carefully tailored to each specific cancer microenvironment.…”

“…In this setting, therapeutic strategies preventing receptor engagement or signaling would revert TA-pDC blockade ( Figure 1 ). Among such strategies, blocking antibodies were developed against LAIR1 ( 179 ), DCIR ( 161 ), ILT2 ( 170 , 171 ), NKp44 ( 155 ) and TIM3 ( 2 ) ( Figure 5A ). As alternative strategies, LAIR1 inhibition was also achieved via an Fc fusion protein of LAIR2, a natural agonist capable of sequestering the ligands ( 181 ) ( Figure 5A ), while DCIR expression was decreased by skin delivery of specific small hairpin RNA ( 162 ) ( Figure 5A ).…”

“…As a matter of facts, TIM3 and, to some extent, ILT2 are already promising emerging targets for checkpoint blockade ( 2 ). Also, DCIR blockade was recently shown to reduce the incidence of experimental inflammation-induced colon carcinoma ( 161 ) and the potential of LAIR1 blockade in cancer immunotherapy is rapidly emerging ( 179 , 182 ). However, these IRs are expressed by different immune and tumor cells and in most studies the neat contribution of pDC rescue in the elicited antitumor response is difficult to deduce or not addressed at all.…”

Blocking Immune Checkpoint—LAIR1: Disrupting the LAIR1—FXIII-A—Collagen Immunosuppressive Circuit for Enhanced Antitumor Therapeutics

“…Previous reports and our results in this study associate LAIR1 expression on M2-like TAM with clinical outcomes (17,18), suggesting LAIR1 is a vital molecule that influences the functionality of M2-like TAM. As a result, there has been a growing interest over the past 3 years among scientists in investigating the role of LAIR1 in cancer progression and its potential as a target for therapeutic drug development (18)(19)(20)(21)(22)(23). Nevertheless, our current knowledge regarding the roles of distinct myeloid cell subsets in tumor progression, as well as the impact of LAIR1 on M2-like TAM functions and response to therapeutic drugs, remains limited.…”