Targeting the Tumor Microenvironment: A New Dawn in Cancer Therapy – KR Pharmtech Advances Next-Generation Pathology with Multiplex Immunohistochemistry

In recent years, immunotherapy has achieved a series of breakthroughs in cancer treatment. With the U.S. FDA’s approval of two CAR-T therapies in 2017, cancer immunotherapy has become a prominent field. Industry experts believe that, owing to its high efficacy and low toxicity, immunotherapy holds promise as the ultimate weapon against cancer.

Research on the tumor microenvironment (TME) is indispensable for cancer immunotherapy.

The tumor microenvironment refers to the internal environment in which tumor cells originate and reside, composed of various cell types and biomolecules. It is closely associated with tumorigenesis, growth, and metastasis. This microenvironment encompasses not only the structural, functional, and metabolic characteristics of the tissue harboring the tumor but also relates to the intrinsic environment of the tumor cells themselves (including the nucleus and cytoplasm). Traditional cancer therapies have primarily focused on the tumor cells themselves; however, as understanding of tumor mechanisms has deepened, the focus of cancer treatment has shifted from the tumor itself to the interactions between the tumor and its surrounding tissues.

Wang Hualiang, Dean of the Shanghai Institute of Experimental Medicine and Director of the Shanghai Clinical Laboratory Center/Quality Control Center, stated to VCBeat: “Research on the tumor microenvironment has emerged as one of the cutting-edge fields in recent years, offering new hope for the diagnosis and treatment of cancer. A growing body of evidence indicates that understanding the expression patterns and functions of immune- and tumor-associated molecules within the context of the tumor microenvironment is crucial for identifying patient populations most likely to benefit from immunotherapy.”Typing the tumor immune microenvironment can better guide clinical treatment and achieve precision medicine.”

However, our current understanding of the tumor microenvironment remains limited, and the vast majority of studies fail to recapitulate the immunosuppressive microenvironment of tumor tissues. There is an urgent clinical need for more effective technologies and approaches to better investigate the tumor immune microenvironment and elucidate the composition of immune cells within tumor tissues.

To address this need, Kuoran Biomedical has developed an efficient and precise solution for comprehensive analysis of the tumor immune microenvironment based on multiplex fluorescent immunohistochemistry technology.

Kuoran Genomics is an early mover in the field of tumor immune microenvironment analysis in China. Bu Lingbin, Chairman of Kuoran Genomics, stated, “We have long focused on the tumor microenvironment, believing that tumor diagnosis and treatment should not only consider the biological characteristics of the tumor itself but also pay attention to the interaction between tumor cells and their surrounding environment.”

“Tumor tissue and surrounding tissues together constitute the tumor microenvironment, which provides the soil for tumor growth, recurrence, and metastasis. This means that tumor detection should not be limited to the genetic level; analysis of the tumor microenvironment is also necessary to effectively predict prognosis, assess treatment response, and achieve precision medicine.”

Unfortunately,For a long time, clinical practice has lacked mature technologies for tumor microenvironment analysis.Traditional techniques, such as immunohistochemistry and flow cytometry, all have certain limitations.

Guo Lingchuan, Director of the Department of Pathology at the First Affiliated Hospital of Soochow University and Chairman of the Pathology Branch of the Jiangsu Medical Association, stated, “Immunohistochemistry plays a crucial role in the histopathological diagnosis of tumors. Only through immunohistochemical analysis of tumor tissues can tumors be definitively characterized and graded. However, despite its widespread application, immunohistochemistry still has certain unavoidable limitations. For instance, only one or two markers can be stained on a single slide, making it difficult to fully capture the true characteristics of highly heterogeneous tumors. Furthermore, although multi-marker staining can be achieved through serial sectioning, this approach fails to accurately analyze correlations between proteins. Most importantly, result interpretation relies primarily on qualitative and semi-quantitative manual assessment, which introduces a degree of subjectivity.”

However, the use of flow cytometry for tumor microenvironment analysis is limited by the loss of cellular morphological information, the inability to interpret the in situ spatial relationships of detected components, and poor accessibility to fresh samples.

Professor Guo Lingchuan affirmed the unique advantages of multiplex fluorescent immunohistochemistry in tumor microenvironment analysis. Based on the principles of TSA staining, this technology overcomes species restrictions for antibodies, enabling immunofluorescent staining of 7–9 biomarkers on a single tissue section. It allows for quantitative assessment of cellular phenotypes and activities, providing a comprehensive characterization of the tumor immune microenvironment and in situ spatial information of intercellular interactions.

Professor Wang Hualiang also expressed optimism about the application potential of multiplex fluorescence immunohistochemistry. “Multiplex fluorescence immunohistochemistry can acquire multi-channel information on cellular composition and spatial arrangement, enabling high-dimensional analysis of the tumor microenvironment. Existing research findings suggest that assessments based on the tumor microenvironment may outperform established biomarkers. Detection of the tumor microenvironment using multiplex fluorescence immunohistochemistry allows for a deeper understanding of tumorigenesis mechanisms and holds greater promise for predicting therapeutic response.”

Due to the high intensity and stability of fluorescent signals, which are resistant to quenching,Multiplex fluorescent immunohistochemistry technology can increase detection sensitivity by 1,000-fold and enable the detection of low-abundance samples,Achieve comprehensive and objective analysis of patient tumor immune subtyping to precisely identify populations likely to benefit from immunotherapy.

Bu Lingbin noted that, in addition to multiplex fluorescent immunohistochemistry, emerging technologies such as spatial transcriptomics, spatial imaging, and mass spectrometry imaging have also drawn significant attention for their potential applications in analyzing the tumor immune microenvironment. “However, these technologies are still in their early stages, with immature technical capabilities and high costs. In contrast, multiplex fluorescent immunohistochemistry is relatively mature, supported by abundant scientific research achievements, and has advanced to the stage of large-scale clinical application.”It is believed that multiplex fluorescent immunohistochemistry will remain the mainstream technology for analyzing the tumor immune microenvironment for a considerable period in the future.”

Professor Guo Lingchuan also stated, “We firmly believe that next-generation pathology technologies, represented by multiplex fluorescence immunohistochemistry, will significantly advance the development and transformation of tumor pathology diagnosis.”

As early as 2019, Kuoran Gene began to lay out the upstream and downstream of the tumor immune microenvironment analysis industry, integrating products and technologies such as multi-marker staining, multispectral imaging systems, and image analysis systems, and launched a panoramic analysis solution for the tumor immune microenvironment.

It is reported that Kuoran Gene’s comprehensive solution for tumor immune microenvironment analysis leverages multiplex fluorescent immunohistochemistry technology, based on Akoya Biosciences’ latest Vectra multispectral quantitative pathology analysis platform. This solution provides a panoramic dissection of the infiltration patterns of cytotoxic T cells, exhausted T cells, macrophages, B cells, NK cells, cytokines, and immune checkpoint receptors within the tumor immune microenvironment. It comprehensively evaluates patient prognosis and therapeutic efficacy of immune checkpoint inhibitor treatment, while elucidating the relationships and clinical molecular mechanisms between the tumor immune microenvironment and tumorigenesis, progression, recurrence, metastasis, and drug resistance.

Clinical trials have shown that,In assessing PD-L1 protein expression levels, Kuoran Gene’s comprehensive solution for tumor immune microenvironment analysis demonstrates strong concordance with the IHC “gold standard” assays (PD-L1 22C3, 28-8, SP142, and SP263), and aids physicians in formulating more precise medication guidance and treatment plans from the perspective of the tumor immune microenvironment.Furthermore, clinical trials have also demonstrated that 10% of colorectal cancer patients exhibit infiltration by double-positive exhausted T cells, and the underlying clinical molecular mechanisms remain to be further validated.

Currently, Kuoran Genomics has established a comprehensive multiplex fluorescent immunohistochemistry technology platform in its Shanghai laboratory, encompassing pathological diagnosis, multiplex staining labeling, multispectral imaging systems, and image analysis systems. The company has developed six assay products for predicting responses to immune checkpoint inhibitors. Validation results have demonstrated high concordance with the approved companion diagnostic product for PD-L1 expression.

Furthermore, Kuoran Genomics has initiated a nationwide cohort study involving 1,000 cases to investigate the tumor immune microenvironment, aiming to further validate the clinical efficacy of its products. The research findings are expected to be released in mid-2022.

Bu Lingbin believes that after nearly five years of development, preliminary basic research has confirmed that multiplex fluorescent immunohistochemistry offers unique advantages in pathological diagnosis, prognosis assessment, and prediction of immunotherapy efficacy. For instance, a study published in JAMA Oncology in 2019 involving 8,000 patients evaluated the predictive value of various biomarkers—including PD-L1, tumor mutational burden (TMB), gene expression profiling (GEP), and the tumor microenvironment—for the efficacy of immune checkpoint inhibitors. The results demonstrated that analysis of the tumor immune microenvironment using multiplex fluorescent immunohistochemistry had the highest predictive value, even surpassing the combined predictive performance of the other three biomarkers.

“Now,Multiplex Fluorescent Immunohistochemistry Technology Is at a Critical Stage of Translating from Research to Application, Kuoran Genomics’ ultimate goal is to accelerate the large-scale clinical application of this technology.We believe that multiplex fluorescent immunohistochemistry will become the next growth driver for pathology departments, following next-generation sequencing (NGS).“said Bu Lingbin.

“But we are well aware that the rapid industrialization and scaling of multiplex fluorescence immunohistochemistry technology cannot rely solely on the efforts of Kuoran Gene.”

Therefore,Kuoran Biomedical has adopted an open-platform strategy, making its multiplex fluorescence immunoassay platform available to partners such as third-party medical testing laboratories, research institutions, and pharmaceutical companies, thereby forming a collaborative alliance.Jointly explore the applications of multiplex fluorescence immunoassay technology in scenarios such as drug efficacy prediction, tumor recurrence risk assessment, and drug development; build a technology-application ecosystem; establish industry consensus; and promote the clinical implementation of multiplex fluorescence immunoassay technology.