Scientific discoveries build on prior research. As new discoveries are made, they often lead to newer research directions in a virtuous cycle. How do scientists know where to begin? How can they focus their efforts on ideas that are starting to gain traction while keeping track of well-covered areas?

By leveraging advanced technologies, CAS scientists use the CAS Content Collection^TM --the largest human-curated repository of scientific information available--to reveal emerging connections between topics, thereby identifying exciting research directions.  

What does this look like in practice? Recently we used a natural language processing (NLP)-based methodology to analyze publications relating to immuno-oncology in the CAS Content Collection. We first developed CAS TrendScape maps that cluster similar concepts together in a readable format. Next, we examined the co-occurrence of concepts in the literature to identify promising intersections that suggest where new breakthroughs are likely to happen. This approach helps researchers focus on emerging ideas and make their next discoveries faster.

How to identify concept co-occurrences

To understand the connections between emerging concepts highlighted in the immuno-oncology CAS TrendScape map, we performed an NLP-based analysis which counts the number of co-occurrences of individual emerging concepts in ​​the same sentences of publication (specifically their abstracts or titles). This approach allowed us to quantify the degree and strength of connection between any two emerging concepts shown in our published CAS TrendScape maps of emerging concepts in immuno-oncology.

We focused this analysis on four major concept pairs:  

• Biomarkers and cancer types
• Therapeutic targets and cancer types
• Therapeutic targets and therapy types
• Therapy types and cancer types

We plotted the number of documents published between 2019 and 2022 where terms co-occurred (x axis) and the average growth rate of publications with these co-occurrences within the same time period (y axis) (see Figure 1).

Our analysis indicated that co-occurring concept pairs tend to fall into one of two extremes:  

• High growth in publications over the last few years but a low overall number of publications (occupying the upper left part of the graph in Figure 1) ‍
• Slower growth in recent publications but a high overall number of publications (occupying the lower right part of the graph in Figure 1).  

The former represents potentially emerging concept pairs while the latter are pairs that are more studied and reported.  

By understanding which ideas are new and gaining momentum, researchers can choose to focus their efforts on potential new breakthroughs.

We applied this methodology to immuno-oncology research because it is a rapidly advancing field in medical science. Immunotherapy offers a promising alternative or complementary strategy to traditional therapies such as chemotherapy and radiation because it leverages the body’s own immune system to recognize and combat cancer cells. This therapeutic approach includes immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines among other strategies.  

The dynamic nature of this field means that this analysis increases the chances for breakthroughs that not only improve survival rates but that can lead to long-term remission and cures for cancer. Let’s examine some examples of emerging research areas across the four major concept pairs:

Biomarkers and cancer types

Understanding biomarkers and their co-occurrence with cancer types enables personalized medicine approaches, tailoring treatments based on individual patient profiles and tumor characteristics. Biomarker-driven clinical trials focus on enrolling patients based on specific biomarker profiles, improving the likelihood of treatment success and accelerating the development of new therapies.  

The co-occurrence of biomarkers and cancer concepts in immuno-oncology publications underscores the complexity and interdependence of immune responses and cancer biology (see Figure 2). Advanced analytical techniques are essential for uncovering these relationships, leading to more effective and personalized cancer immunotherapies.

• Tumor-mutational burden (TMB) is a biomarker that quantifies the number of mutations within a tumor genome. It is gaining importance in immuno-oncology as a predictor of response to ICIs, and we see significant growth in the TMB-colon cancer concept pair. High TMB is associated with a higher likelihood of producing neoantigens, which can make tumors more recognizable and targetable by the immune system. ICIs, such as PD-1/PD-L1 inhibitors, work by unleashing the immune system to attack cancer cells. High TMB can enhance the effectiveness of ICIs by increasing the number of targets (neoantigens) available for immune recognition.
• The nectin-4-bladder cancer concept pair shows an upward trend with a six-fold increase in publications between 2020 and 2022. Nectin-4 is a cell adhesion molecule that plays a role in the formation of cell-cell junctions. It is highly expressed in urothelial carcinoma, the most common type of bladder cancer. Its overexpression is associated with tumor progression and poor prognosis. High levels of nectin-4 expression can be used as a diagnostic marker for bladder cancer, helping to identify patients who may benefit from targeted therapies. ‍

‍Therapeutic targets and cancer types

The identification of targets in cancer treatment has become a cornerstone of precision oncology, aiming to develop therapies that specifically target cancer cells while sparing normal tissues. The concept of targets in cancer refers to protein molecules or pathways that play crucial roles in cancer cell survival and growth. By understanding and exploiting these targets, researchers and clinicians can design treatments that are more effective and have fewer side effects than traditional therapies.

The co-occurrence of targets and cancer types refers to the interplay between molecular targets and the characteristics of different cancers. Understanding these relationships is crucial for developing effective therapies and improving patient outcomes. As seen in Figure 3, several co-occurrences have spiked in recent years:

• The m⁶A-lung cancer concept pair co-occurrence exhibits the highest average fold increase in publications (nearly 4.5-fold) of all therapeutic target and cancer type concept pairs, which spotlights it as an emerging topic pair in immuno-oncology. The pair shows a marked increase in publications after 2019, growing eight-fold over a two-year period.  

This RNA modification, also known as N6-methyladenosine, influences tumor development, progression, and response to therapy. These modifications can also contribute to drug resistance in lung cancer. Understanding these mechanisms may help in developing strategies to overcome resistance.

• The PD-1-liver cancer concept pair is an example of co-occurring concepts that increased at a modest average rate (two-fold) over the period 2020-2022 while having a relatively high number of publications overall, indicating that it is perhaps more well-established than the other concepts. Liver cancer has been a significant focus in immuno-oncology due to the unique liver immune environment and the high prevalence of chronic liver diseases that predispose it to cancer development. Liver immune tolerance is primarily regulated by various mechanisms, including the PD-1/PD-L1 pathway, which helps prevent autoimmunity but can also facilitate immune evasion by liver tumors.

Therapeutic targets and therapy types

The co-occurrence of therapeutic targets and therapy types reveals important relationships and insights into how different therapeutic strategies are developed and applied. This involves studying specific molecular targets, immune pathways, and types of therapies being investigated and used in cancer treatment (see Figure 4).

• The high increase (>4.5-fold) in the NK cell-STING agonist concept pair indicates growing interest from the scientific community in recent years. NK cells are a type of lymphocyte that play a crucial role in the innate immune response, particularly in recognizing and killing virally infected cells and tumor cells. In the context of immuno-oncology, NK cells are recognized for their ability to target and eliminate cancer cells without the need for prior sensitization to tumor antigens.  

The stimulator of interferon genes (STING) pathway is a critical component of the innate immune response, particularly in the detection of cytosolic DNA from pathogens or damaged cells, which can occur in cancer. Activation of STING leads to the production of type I interferons and other cytokines, which can enhance the anti-tumor immune response by promoting the activation of dendritic cells, T cells, and NK cells.  

• The TROP2-ADC concept pair doesn’t have the same precipitous growth as NK cells-STING agonist, but it’s been increasing quickly over the last few years. Trophoblast cell-surface antigen 2 (TROP2), also known as tumor-associated calcium signal transducer 2 (TACSTD2), is a cell surface glycoprotein that plays a role in cell signaling, proliferation, and survival. TROP2 is expressed at low levels in normal tissues but is overexpressed in a many cancers, including breast, lung, colorectal, pancreatic, and prostate. This overexpression makes TROP2 a valuable target in cancer therapy, particularly for antibody-drug conjugates (ADCs).

Therapy types and cancer types

In immuno-oncology, the co-occurrence of therapy types and cancer types provides valuable insights into the interconnectedness of various therapeutic strategies and their applications across different malignancies. Analyzing these co-occurrences helps identify effective therapeutic strategies, research trends, and potential areas for future investigation. This understanding is crucial for developing more effective and personalized cancer immunotherapies, improving patient outcomes (see Figure 5).

• Traditionally, liver cancer has been challenging to treat, with limited options for advanced stages. The introduction of ICIs has provided new hope for patients with liver cancer, and the immune-checkpoint antibodies-liver cancer concept pair is one of the top emerging ideas.

In liver cancer, ICIs work by blocking the interaction between PD-1 on T cells and PD-L1 on tumor cells, removing the "brake" on the immune system and allowing T cells to attack and destroy cancer cells. The most common ICIs target PD-1, PD-L1 (Programmed Death-Ligand 1), and CTLA-4.  

• The CAR-T-multiple myeloma (MM) concept pair is an example of a maturing concept, as seen by its placement farther to the right in the graph (Figure 5) yet still with a relatively high average-fold increase in recent years. The success of CAR-T therapy depends on identifying suitable target antigens that are abundantly expressed on cancer cells but not on healthy cells. For MM, the most prominent target is B-cell maturation antigen (BCMA), a protein highly expressed on MM cells that is the most widely studied and targeted antigen in CAR-T therapy for MM. BCMA is the primary target, but other antigens such as SLAMF7, CD19, CD138, and GPRC5D are also being explored for CAR-T therapy, particularly in patients who relapse after BCMA-targeted therapy.

Immuno-oncology breakthroughs on the horizon

As our analysis of the CAS Content Collection shows, there are numerous emerging ideas in  immuno-oncology that have the potential to revolutionize treatment options and improve patient outcomes. As more research is carried out, it may become difficult for researchers to pinpoint new areas ripe for exploration. Our analysis of co-occurring concept pairs facilitates research breakthroughs by showing which ideas are getting noticed and which are more mature especially in the context of other emerging topics.

These research directions are valuable in any field, but in a rapidly evolving one like immuno-oncology, which has life-saving impacts on patients, they are crucial to help the medical community bring better cures to patients faster.  

To learn more about the co-occurring emerging concepts in immuno-oncology, see our publication at a pre-print server.