Hope for PD-(L)1 Resistance?

CAFs are a significant factor in PD-1 resistance, with LRRC15+ CAFs being a critical subgroup. Anti-LRRC15 provides a new strategy for PD-(L)1 resistance, and several drugs are currently under development.

LRRC15 Structure and Function

LRRC15 is a transmembrane protein located on chromosome 3q29 and belongs to the leucine-rich repeat (LRR) superfamily. It participates in cell-cell and cell-extracellular matrix (ECM) interactions. In healthy tissues, its expression is limited to specific areas such as the placenta, hair follicles, tonsils, certain regions of the stomach, spleen, osteoblasts, and wound healing sites. In tumors, LRRC15 is highly expressed in cancer-associated fibroblasts (CAFs) of various solid tumors and mesenchymal-origin tumors (such as sarcomas, glioblastomas, and melanomas). Studies have shown that LRRC15 plays a role in cancer metastasis; for example, in ovarian cancer, its expression is associated with tumor metastasis, chemotherapy resistance, and shortened overall survival. LRRC15 can also activate focal adhesion kinase signaling pathways to promote metastasis by interacting with fibronectin and β1 integrin.

LRRC15 and PD-1

LRRC15 and Tumor Immune Evasion and Its Impact on PD-1 Immunotherapy

High expression of LRRC15 is associated with immune therapy resistance. Several papers have shown that LRRC15 is highly expressed in various solid tumors and is linked to immune evasion. In the study "Key Regulatory Elements of the TGFβ-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types," the high expression of LRRC15 and its activating genes (MMP2, SPARC, TGFβR2, WNT5B) is associated with immune therapy resistance and poor prognosis. It can predict patient survival and immunotherapy response. In tumors like lung squamous cell carcinoma, renal clear cell carcinoma, and metastatic bladder cancer, patients with high expression of these five genes have poor survival outcomes after immunotherapy. In "LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity," the study found that the high expression of LRRC15+ CAF gene signatures is associated with a lack of response to anti-programmed death ligand 1 (PDL1) immune checkpoint blockade therapy.

LRRC15 Affects Tumor Microenvironment to Suppress T Cell Function

LRRC15+ CAFs in the tumor microenvironment can directly suppress CD8+ T cell function, limiting their ability to kill tumor cells. Experiments in genetically engineered mouse models show that selective depletion of LRRC15+ CAFs can alleviate the direct suppression of tumor-infiltrating CD8+ T cells, enhancing their effector functions and promoting tumor regression. Tumor cells express PD-L1, which binds to PD-1 on the surface of T cells, inhibiting T cell activity and allowing tumor cells to escape immune system attacks. The presence of LRRC15+ CAFs may further exacerbate this immunosuppressive microenvironment, impacting the effectiveness of PD-1 immunotherapy.

Therapeutic Strategies Targeting LRRC15 and PD-1 and Research Progress

LRRC15-Targeted Therapeutic Drugs

The article "Exploiting LRRC15 as a Novel Therapeutic Target in Cancer" details ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15. It consists of an anti-LRRC15 humanized IgG1 antibody and the anti-mitotic drug monomethyl auristatin E (MMAE) linked via a cleavable valine-citrulline (vc) linker. Preclinical studies show that ABBV-085 has significant efficacy in LRRC15-positive tumor models, inhibiting tumor growth both as a monotherapy and in combination with other therapies. It has shown good activity in various solid tumor xenograft models. Phase I clinical trials show that it is well-tolerated and demonstrates preliminary antitumor activity in refractory tumors like sarcomas. Other LRRC15-targeted ADCs have also shown potential in preclinical studies, such as LRRC15-PNU in osteosarcoma models, with a cure rate ranging from 40% to 100%.

Mechanism and Application of PD-1 Inhibitors

The design of PD-1 inhibitors involves administering antibodies targeting PD-1 or PD-L1 to tumor patients to block the binding of PD-1 with its ligand, thereby activating the body's immune system and allowing T cells to recognize and attack cancer cells. Currently, several PD-1 inhibitors have been approved by the FDA, with indications covering various tumors. In certain tumor treatments, PD-1 inhibitors used alone or in combination with other therapies have shown efficacy.

Exploration of Combination Therapy

As LRRC15+ CAFs are associated with immune therapy resistance, researchers have started exploring combination therapies targeting both LRRC15 and PD-1. In "LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity," experiments showed that in LRRC15+ CAF-depleted mice, treatment with anti-PD-L1 antibody led to more significant tumor growth inhibition and prolonged survival. This suggests that combination therapy may improve tumor treatment outcomes and provide better prognosis for cancer patients.

Some LRRC15 Drugs

• ABBV-085: An anti-LRRC15 ADC developed by AbbVie, with MMAE as the toxin. It has shown preliminary antitumor activity in osteosarcoma and undifferentiated pleomorphic sarcoma patients, with an overall response rate of 20%, but limited efficacy in non-sarcoma patients.
• ZL-6201: A novel LRRC15 ADC drug developed by Zai Lab and EdiGene, showing encouraging data in preclinical studies.
• H02L01-V1-PBD: A targeted LRRC15 ADC drug developed by Synaffix, with PBD as the toxin. It has shown superior antitumor activity in preclinical studies compared to ABBV-085.
• QL315: A bispecific antibody developed by Qilu Pharmaceutical, designed to target both CD3 and LRRC15. It has shown strong T cell activation and tumor cell lysis in vitro and suppressed tumor growth in mouse xenograft models. However, QL315 has been removed from the development pipeline.
• LNTH-2403: A radiopharmaceutical targeting LRRC15 developed by Lantheus/Radiopharm, currently in preclinical stages, with FDA orphan drug designation for osteosarcoma treatment.
• Bonum Therapeutics Fusion Protein Drugs: Bonum Therapeutics has developed two LRRC15 fusion protein drugs to expand the therapeutic applications of this target, although limited public information is available on these drugs' development progress.

Reference

[1]. Krishnamurty AT, Shyer JA, Thai M, Gandham V, Buechler MB, Yang YA, Pradhan RN, Wang AW, Sanchez PL, Qu Y, Breart B, Chalouni C, Dunlap D, Ziai J, Elstrott J, Zacharias N, Mao W, Rowntree RK, Sadowsky J, Lewis GD, Pillow TH, Nabet BY, Banchereau R, Tam L, Caothien R, Bacarro N, Roose-Girma M, Modrusan Z, Mariathasan S, Müller S, Turley SJ. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature. 2022 Nov;611(7934):148-154. doi: 10.1038/s41586-022-05272-1. Epub 2022 Sep 28. PMID: 36171287; PMCID: PMC9630141.

[2]. Lavie D, Ben-Shmuel A, Erez N, Scherz-Shouval R. Cancer-associated fibroblasts in the single-cell era. Nat Cancer. 2022 Jul;3(7):793-807. doi: 10.1038/s43018-022-00411-z. Epub 2022 Jul 26. PMID: 35883004; PMCID: PMC7613625.