TPS3167 Background: B7-H4 is a transmembrane receptor of the B7-family of immunomodulatory proteins whose expression correlates with poor clinical outcomes for ovarian and breast cancers. High expression in multiple tumor types and limited expression in normal tissues makes B7-H4 an attractive target for antibody drug conjugate (ADC) therapeutics. LNCB74 is a B7-H4 targeted ADC in which a humanized IgG1κ antibody is conjugated to the microtubule disrupting payload monomethyl auristatin E (MMAE) with a drug-to-antibody ratio of 4 (DAR4). LNCB74 is designed to maximize therapeutic index through three key elements. First, site specific ConjuAll conjugation results in a homogeneous DAR to drive uniform PK. Second, our proprietary glucuronidase-cleavable linker reduces both on- and off-target toxicity. Third, the antibody Fc was “LALA”-mutated to reduce Fc mediated uptake into Fc receptor expressing cells such as immune and endothelial cells. Compared to other B7-H4 targeted ADCs in clinical development, LNCB74 has demonstrated a superior safety profile in nonhuman primate toxicity studies and potent anti-tumor activity in multiple cell line- and patient-derived xenograft in vivo models, making it a promising ADC therapy for B7-H4-expressing solid tumors. Methods: LNCB74-01 is a phase 1, open-label, first-in-human study that will include dose escalation, safety, and biomarker backfills (Part 1) and randomized dose expansion/optimization (Part 2). The objectives of the study will be to determine safety and tolerability, define the maximum tolerated dose and/or recommended phase 2 dose, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and to assess the preliminary efficacy in participants with metastatic solid tumors treated with LNCB74. The tumor types include ovarian, breast, endometrial, biliary tract cancer, and squamous NSCLC. Key eligibility criteria include measurable disease based on RECIST v1.1 and the ability to provide tissue samples to test B7-H4 expression by CLIA-certified immunohistochemistry assay in a central laboratory. Participants will receive LNCB74 on Day 1 of each 21-day cycle. Dose escalation will follow a Bayesian optimal interval (BOIN) design. Dose expansion will occur in up to two tumor types. In each tumor specific dose expansion, participants will be randomized to two dose levels stratifying for prior lines of therapy (1-3 vs ≥4) and B7-H4 expression (intermediate vs high). The PK profile, immunogenicity, preliminary anti-tumor activity per RECIST v1.1, and correlation of baseline B7-H4 expression to anti-tumor activity of LNCB74 will be evaluated as secondary endpoints. Biomarkers will be assessed in peripheral blood and tumor tissue. Enrollment is ongoing in the United States. Clinical trial information: NCT06774963 .

We previously observed that circulating human neutrophils exposed to epithelial ovarian cancer (OC) ascites fluid supernatants (ASC) and malignant effusions from other tumors acquire T cell suppressor function. Collagen motifs ligate LAIR-1, an inhibitory SHP-1-dependent checkpoint broadly expressed on immune cells. We hypothesized that NC410, a bivalent LAIR-2 construct that inhibits LAIR-1-collagen binding, would rescue neutrophil-driven T cell non-responsiveness. NC410 remodeled ASC collagen resulting in neutrophil clustering and reduction in neutrophil-T cell contact, abrogated ASC-induced neutrophil trogocytosis of T cell membranes and rescued stimulated T cell proliferation. Mean ASC pro-collagen-1α levels were >100-fold greater than serum samples. In a single-center retrospective analysis, after adjusting for age, stage and optimal debulking, ASC pro-collagen-1α and serum sLAIR-1 levels were each associated with worse overall survival (OS), and ASC LAIR-2 levels were associated with better OS. Multispectral imaging of high-grade serous ovarian cancer and non-small cell lung cancer showed highly variable LAIR-1 staining in both tumor cell and immune infiltrates. The proportion of collagen-1-positive cells was highest among tumor cells and tumor-infiltrating immune cells versus stromal immune cells, raising the potential role of tumor-associated collagen limiting immune cell infiltration into tumor. Our results support further evaluation of circulating and tumor-associated collagen products and LAIR-1 and LAIR-2 as prognostic biomarkers in advanced OC and as biomarkers for clinical response to NC410 and to other collagen- and LAIR-directed therapies.

e15022 Background: LAIR-1 is a receptor expressed on the surface of hematopoietic cells subsets that negatively regulates immune activity. It is also highly and broadly expressed on the surface of many leukemia and lymphoma cells. Differential signaling of LAIR-1 in leukemia can confer a survival advantage to these cancer cells. These features make LAIR-1 an attractive therapeutic target in hematologic cancers. Previous studies have shown that a LAIR-1 targeting agonist antibody induced leukemic cell death. Here, we sought to determine if targeting LAIR-1 with an antibody drug conjugate (ADC) would be safe and efficacious in hematologic cancers expressing LAIR-1. Methods: LAIR-1 expression was assessed in leukemias and lymphomas by IHC and RNA. In vitro assays were run to screen for internalization of a LAIR-1 monoclonal antibody (mAb) in tumor cell lines and PBMCs. The LAIR-1 mAb was conjugated with various cytotoxic payloads to evaluate in vitro killing of leukemic cells, as well as for safety in mice engineered to express the human LAIR-1 extracellular region under the endogenous LAIR-1 promoter, and retaining murine transmembrane and cytoplasmic regions. The LAIR-1 mAb conjugated with various payloads was tested in human patient cell-line derived (CDX) tumor models of leukemia and lymphoma for anti-tumor activity. Results: LAIR-1 was broadly and highly expressed in AML. Some T cell lymphomas also expressed high levels of LAIR-1. LAIR-1 was rapidly internalized in vitro in tumor cells but not human PBMCs. An in vitro cytotoxicity assay testing a LAIR-1 ADC mAb killed tumor cells dependent on the level of LAIR-1 expression. Safety was tested in human LAIR-1 knock-in (KI) mice since the LAIR-1 mAb does not cross-react with murine LAIR-1. Human LAIR-1 KI blood and spleen immune cell populations and frequencies did not change following treatment with LAIR-1 ADC, and various payloads conjugated to LAIR-1 showed no toxicity of any ADCs based on weight loss. Various LAIR-1 ADCs were tested for activity in both leukemia and lymphoma in vivo CDX tumor models. Potent regression and control of tumor was observed with LAIR-1 ADC in comparison to naked LAIR-1 mAb and control. Conclusions: LAIR-1 ADCs appear safe in human LAIR-1 KI mice. LAIR-1 ADC was highly effective in eradicating and controlling both leukemia and lymphoma tumors that expressed LAIR-1. Together, this study supports the development of a LAIR-1 ADC for the treatment of LAIR-1 expressing hematological cancers.

The immune system maintains the health of an organism through complex sensing and communication mechanisms. Receptors on the surface of immune cells respond to stimuli resulting in activity described at its most basic as inhibitory or stimulatory. Significant progress in therapeutic intervention has occurred by modulating these pathways, yet much remains to be accomplished. Therapeutics that antagonize, or block, immune inhibitory receptor (IIR) pathways, such as checkpoint inhibitors in cancer are a key example. Antagonism of immune stimulatory receptors (ISRs) for dysregulated inflammation and autoimmunity have received significant attention. An alternative strategy is to agonize, or induce signaling, in immune pathways to treat disease. Agonism of ISRs has been employed with some success in disease settings, but agonist therapeutics of IIRs have great, untapped potential. This review discusses and highlights recent advances in pre-clinical and clinical therapeutics designed to agonize IIR pathways to treat diseases. In addition, an understanding of IIR agonists based on activity at a cellular level as either agonist suppression of stimulatory cells (SuSt), or a new concept, agonist suppression of suppressive cells (SuSu) is proposed.

Cancers exploit coinhibitory receptors on T cells to escape tumor immunity, and targeting such mechanisms has shown remarkable clinical benefit, but in a limited subset of patients. We hypothesized that cancer cells mimic noncanonical mechanisms of early development such as axon guidance pathways to evade T cell immunity. Using gain-of-function genetic screens, we profiled axon guidance proteins on human T cells and their cognate ligands and identified fibronectin leucine-rich transmembrane protein 3 (FLRT3) as a ligand that inhibits T cell activity. We demonstrated that FLRT3 inhibits T cells through UNC5B, an axon guidance receptor that is up-regulated on activated human T cells. FLRT3 expressed in human cancers favored tumor growth and inhibited CAR-T and BiTE + T cell killing and infiltration in humanized cancer models. An FLRT3 monoclonal antibody that blocked FLRT3-UNC5B interactions reversed these effects in an immune-dependent manner. This study supports the concept that axon guidance proteins mimic T cell checkpoints and can be targeted for cancer immunotherapy.

Abstract Our understanding of molecular cell-surface interactions that control T cell responses in cancer remains limited despite many advances in the field. We hypothesized that tumor cells take advantage of developmental protein-protein interactions such as axon guidance interactions that could inhibit or repel tumor-immune interactions in the TME to evade T cell anti-tumor immunity. We used gain-of-function screening to evaluate a gene-set of axon guidance proteins for inhibitory function in human T cells and identified and validated Fibronectin and Leucine-Rich Transmembrane protein-3 (FLRT3) as an inhibitor of T cell activity. FLRT3 inhibited human T cell function and promoted tumor growth in humanized tumor cell-derived xenograft (CDX) models. FLRT3 inhibited T cells through interaction with Unc-5 Netrin Receptor B (UNC5B) expressed on activated T cells. A FLRT3 monoclonal antibody designed to specifically block FLRT3 interactions with UNC5 family proteins reduced tumor growth in CDX models that was dependent on T cells. FLRT3 blockade also enhanced CAR-T and BiTE + T cell activity and infiltration in humanized zebrafish tumor models. These studies support the notion that aberrant axon guidance protein expression in the TME act as T cell checkpoints, and the FLRT3:UNC5B pathway can be targeted therapeutically to improve T cell-based immunotherapy activity and infiltration.

Collagen expression and structure in the tumour microenvironment are associated with tumour development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor. LAIR-2 is a soluble homologue of LAIR-1 that competes for collagen binding. Multiple studies in mice implicate blockade of LAIR-1:collagen interaction in cancer as a promising therapeutic strategy. Here, we investigated the role of LAIR-1 in anti-tumour responses. We show that although LAIR-1 inhibits activation, proliferation, and cytokine production of mouse T cells in vitro, tumour outgrowth in LAIR-1-deficient mice did not differ from wild type mice in several in vivo tumour models. Furthermore, treatment with NC410, a LAIR-2-Fc fusion protein, did not result in increased tumour clearance in tested immunocompetent mice, which contrasts with previous data in humanized mouse models. This discrepancy may be explained by our finding that NC410 blocks human LAIR-1:collagen interaction more effectively than mouse LAIR-1:collagen interaction. Despite the lack of therapeutic impact of NC410 monotherapy, mice treated with a combination of NC410 and anti-programmed death-ligand 1 did show reduced tumour burden and increased survival. Using LAIR-1-deficient mice, we showed that this effect seemed to be dependent on the presence of LAIR-1. Taken together, our data demonstrate that the absence of LAIR-1 signalling alone is not sufficient to control tumour growth in multiple immunocompetent mouse models. However, combined targeting of LAIR-1 and PD-L1 results in increased tumour control. Thus, additional targeting of the LAIR-1:collagen pathway with NC410 is a promising approach to treating tumours where conventional immunotherapy is ineffective.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.

Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types.

Abstract The significant albeit limited clinical benefit of therapeutic targeting of checkpoint inhibitors highlights the need for immunological understanding of cancer escape from anti-tumor immunity to develop novel and better therapeutics. We surmise that many protein-protein interactions that regulate T cell immunity have yet to be identified. Using human gain-of-function genetic screens, thousands of proteins were screened for their ability to inhibit primary human T cell function. B Cell Adhesion Molecule (BCAM) was identified as a potent inhibitor of T cell proliferation and cytotoxic T cell (CTL) ability to kill human tumors in vitro. Tumor cell surface BCAM inhibited anti-tumor immunity promoted tumor growth in vivo. Blockade with decoy soluble BCAM protein fused to a either a silenced or functional Fc domain (BCAM Fc fusion protein) was able to promote T cell anti-tumor immunity and reduce tumor growth in syngeneic and humanized CDX tumor models. Moreover, tumor BCAM interaction with known ligand Laminin-a5 (LAMA5) resulted in increased production of LAMA5 that was associated with ECM modifications and potent exclusion of T cells from the tumor microenvironment (TME). BCAM Fc disruption of BCAM-LAMA5 interactions resulted in decreased LAMA5 production, increased T cell infiltration and decreased tumor growth. These data support a multi-pronged role for BCAM in anti-tumor T cell suppression and exclusion that can be targeted therapeutically.

2538 Background: Treatment options for advanced, refractory MSS/MSI-L CRC and Ovarian cancer are limited, with no FDA-approved ICI therapies. Such tumors have higher collagen deposition resulting in inherent resistance to ICI therapy partly due to the tumor extracellular matrix (ECM) functioning as a physical barrier to immune cell infiltration. Furthermore, dysregulated collagen in ECM inhibits immune cell function through binding to the inhibitory receptor, Leukocyte Associated Immunoglobulin-Like Receptor-1 (LAIR-1) expressed on immune cells. This inhibition can be reversed by endogenous LAIR-2 decoy protein, that competes with LAIR-1 binding. NC410 is a dimeric LAIR-2 protein fused to a human IgG1 Fc domain. NC410 promotes ECM remodeling by targeting collagen, promoting immune cell infiltration, and reversing LAIR-1-mediated immunosuppression. In preclinical models, NC410 in combination with anti-PD-1/anti-PD-L1 further potentiates immune function and anti-tumor activity in recalcitrant tumors. Methods: An open-label, single-arm Phase 1b/2 study was initiated to determine the safety, tolerability, and RP2D of NC410 when combined with pembrolizumab in metastatic solid tumors (NCT05572684). Participants received a fixed dose of pembrolizumab (400mg Q6W) on Day 1 and NC410 Q2W on Days 1, 15, and 29 of each 42-day cycle following a modified Toxicity Probability Interval (mTPI) design. The data cut-off was 4-Jan-2024 and the study continues to enroll. Results: To date, 65 participants with ICI naïve and refractory MSS/MSI-L CRC and Ovarian cancer received escalating doses of NC410 at 30 (n=3), 60 (n=11), 100 (n=39), and 200mg (n=12) in combination with pembrolizumab. The therapy appears safe and tolerable with diarrhea and fatigue being the most common, and Gr≥3 treatment emergent (14.8%) and related (1%) adverse events; one participant discontinued study due to myocarditis (Gr 3). Of the 32 MSS/MSI-L CRC treated with 100mg NC410, 28 are ICI naïve, of which 17 are currently evaluable with at least one 9-week scan. Of the 17, two confirmed PRs remain ongoing (>9 mo and > 4 mo), 6 durable SD (DCR 47%, ≥ 4 months), and 9 reported PD. Of the 11 Ovarian treated, 9 are currently evaluable: 2 ongoing PRs (>6mo at 200mg and 2mo at 100mg), 2 durable SD ≥4 months at 60mg NC410, and 5 PD. Preliminary assessment of pre- and on-treatment biopsies (N=12) shows decrease in immature collagen, suggesting ECM remodeling. Pre- and on-treatment peripheral blood immunophenotyping shows relatively higher CD8+ effector memory T cells and lower myelosuppressive neutrophils in CRC subjects without liver metastasis. Conclusions: Taken together, NC410 in combination with pembrolizumab shows promising clinical activity in hard-to-treat, advanced metastatic CRC and Ovarian cancer. Clinical trial information: NCT05572684 .

Sig15 promotes an immunosuppressive tumor microenvironment in B-ALL. A–M, Unirradiated WT C57BL6 mice were injected via tail vein with 5 × 105 Cas9-only (n = 8 from two independent experiments) or Sig15 KO (n = 8) leukemia. Bone marrow was harvested 7 days later for highly dimensional flow cytometry of non-leukemia bone marrow populations. Healthy, leukemia-naïve mice (Naive) were included as controls (n = 6). CD3+ T cells (A), NK cells (B), classical dendritic cells (cDC; C), and neutrophils (D) were variably present at higher totals in the bone marrow of Sig15 KO recipient mice compared with control leukemia. E, Representative contour plots of T-cell populations. Proportions of CD8+ (F) but not CD4+ (G) T cells were higher in Sig15 KO recipients than control leukemia, increasing the CD8+/CD4+ T-cell ratio (H) to levels comparable with Naive mice. I, Degranulated CD8+ T cells were higher in Sig15 KO recipient mice, as were SLEC (J) and MPEC (K) CD8+ T-cell populations. Early memory-like populations consistent with central (L) and effector memory (M) CD8+ T-cell populations were also higher in Sig15 KO recipients. N–P, From the same experiments, bone marrow supernatant from control and Sig15 KO leukemia recipient mice was analyzed via 44-plex cytokine/chemokine assay. Levels of IL6 (N), LIF (O), and IL5 (P) were all significantly lower in the bone marrow of Sig15 KO recipients as compared with control leukemia (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Sig15 expression on B-ALL cells suppresses CD8+ T-cell expansion and activation and contributes overall to formation of a more proleukemia bone marrow microenvironment.

Siglec-15 (Sig15) has been implicated as an immune checkpoint expressed in solid tumor-infiltrating macrophages and is being targeted in clinical trials with mAbs to normalize the tumor immune microenvironment and stimulate antitumor immunity. However, the role of Sig15 in hematologic malignancies remains undefined. Sig15 mRNA and protein expression levels in hematologic malignancies were determined from publicly available databases, cell lines, and primary patient samples. Human B-cell acute lymphoblastic leukemia (B-ALL) cell lines were used to identify signaling pathways involved in the regulation of Sig15 expression. Secreted/soluble Sig15 and cytokine levels were measured from the plasma of children with leukemia and healthy controls. Knockdown and knockout of Siglec15 in a murine model of B-ALL was used to evaluate the effect of leukemia-derived Sig15 on the immune response to leukemia. We observed pathologic overexpression of Sig15 in a variety of hematologic malignancies, including primary B-ALL samples. This overexpression was driven by NFκB activation, which also increased the surface localization of Sig15. Secreted/soluble Sig15 was found to circulate at elevated levels in the plasma of children with B-ALL and correlated with an immune-suppressive cytokine milieu. Genetic inhibition of Sig15 in murine B-ALL promoted clearance of the leukemia by the immune system and a marked reversal of the immune-privileged leukemia bone marrow niche, including expanded early effector CD8+ T cells and reduction of immunosuppressive cytokines. Thus, Sig15 is a novel, potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate T lymphocytes against leukemia cells. Significance: We demonstrate that Sig15 is overexpressed in hematologic malignancies driven by NFκB, is required for immune evasion in a mouse model of leukemia, and, for the first time, that it circulates at high levels in the plasma of children with leukemia.

LAIR-1 expression in different molecular subtypes of within Storma and Tumor. (A) Umap (Uniform Manifold Approximation and Projection) plot showing the expression of LAIR-1 RNA in patient lung tumor biopsies (n=7) derived single cell RNA-seq data. (B) Quantification of LAIR-1 expression in LM22 immune cells showing highest expression of LAIR-1 in macrophages.

ABSTRACT Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐15 is expressed on the cell surface of mature osteoclasts. Anti‐Siglec‐15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec‐15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4‐month‐old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, −18.7%), trabecular bone volume (−43.1%), trabecular connectivity (−59.7%), and bone stiffness (−76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec‐15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Targeting the interaction of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) and its ligands has been shown to reinstate antitumor immunity. In addition, the introduction of the LAIR-1 decoy protein, LAIR-2, sensitizes previously resistant lung tumors to programmed death-1 (PD-1) blockade, indicating the potential of LAIR-1 as an alternative marker for anti-PD-1 resistance in lung cancer. Here, we assessed LAIR-1 as compared with programmed death-ligand 1 (PD-L1) expression in various tumors, with a focus on non–small cell lung cancer (NSCLC) and its histologic subtypes using multiplexed quantitative immunofluorescence (mQIF) in 287 (discovery cohort) and 144 (validation cohort) patients with NSCLC. In addition, using multispectral imaging technology on mQIF images, we evaluated the localization of LAIR-1 on various cell types. We observed that CD14+, CD68+, and CD163+ monocytes and CK+ tumor cells predominantly expressed LAIR-1 more than other cell types. Furthermore, LAIR-1 expression in the tumor compartment was significantly higher in patients with lung adenocarcinoma (LUAD) than those with lung squamous cell carcinoma subtype (**, P = 0.003). Our results indicated that high tumor LAIR-1 expression in patients with LUAD is negatively associated with OS (overall survival, HR = 2.4; *, P = 0.02) highlighting its prognostic value in LUAD but not in other subtypes. The Pearson correlation between LAIR-1 and PD-L1 is 0.31; however, mutual exclusive staining pattern (i.e., several cases were positive for LAIR-1 and negative for PD-L1) was observed. Altogether, our data suggest that the combination therapy of anti-PD-1/PD-L1 with anti-LAIR-1 or the anti-LAIR-1 monotherapy alone may be promising cancer immunotherapeutic strategies.Significance:The spatial, quantitative assessment of LAIR-1 in NSCLC shows positive association of OS with high LAIR-1+/CD68+ cell densities and negative association of OS with high LAIR-1 expression in LUAD tumor subtype.

Sig15 is required for immune evasion by murine B-ALL.