Shedding light on why immunotherapy sometimes fails

Researchers discover that some antibody-based therapies can have off-target effects, impairing the immune system’s ability to fight off cancer

Chiba University

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10F.9G2, a monoclonal antibody with high antibody-dependent cellular cytotoxicity, has an off-target effect that involves the reduction of CD8+ T cells. This surpasses the on-target effect, namely programmed cell death protein 1/programmed death-ligand 1 axis inhibition, resulting in no observable antitumor efficacy. In contrast, MIH6, which has low antibody-dependent cellular cytotoxicity activity, exerts only the on-target effect, leading to an effective antitumor response.

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Credit: Assistant Professor Yuta Tamemoto from Chiba University, Japan Source link: https://www.sciencedirect.com/science/article/pii/S0378517325005927?via%3Dihub

Immune checkpoint inhibitors (ICIs), a powerful form of immunotherapy, have revolutionized cancer treatment by unleashing the body’s own immune system to fight tumors. These compounds target the programmed cell death-ligand 1 (PD-L1), a surface protein typically found on tumor cells, which enables the tumors to avoid recognition by immune T cells. By disrupting PD-L1’s function with specially tailored antibodies, ICI-based strategies have brought hope to countless patients with cancer. However, despite their undeniable success, these treatments do not work for everyone. Many patients remain unresponsive to immunotherapy, and scientists have been struggling to understand why some people benefit while others don’t. 

While much research has focused on tumor and patient characteristics that could influence treatment response, less attention has been paid to how the drugs themselves might influence their treatment success. Different antibody drugs, even those targeting the same immune pathway, may have varying properties that subtly or dramatically impact their effectiveness. These include differences in how long they stay in the body, how well they reach tumors, and perhaps most importantly, what other cellular functions they might trigger beyond their intended target.

Against this backdrop, a research team led by Assistant Professor Yuta Tamemoto and Professor Hiroto Hatakeyama from the Graduate School of Pharmaceutical Sciences at Chiba University, Japan, investigated what factors affect the performance of anti-PD-L1 antibodies. Their findings were made available online on May 22, 2025, and were published in Volume 679 of the International Journal of Pharmaceutics on June 30, 2025.

The researchers set out to understand why two different anti-PD-L1 monoclonal antibodies, both designed to block cancer’s immune evasion via the same mechanism, showed vastly different results in laboratory models. In particular, they focused on a powerful immune response called antibody-dependent cellular cytotoxicity (ADCC). Simply put, ADCC is a mechanism that triggers when a cell is covered in antibodies; this elicits a strong immune response that leads to the death of the cell, usually mediated by natural killer cells.

The team compared two specific anti-PD-L1 monoclonal antibodies: MIH6, which has minimal ADCC activity, and 10F.9G2, which exhibits strong ADCC activity. In a mouse tumor model, MIH6 was remarkably effective, inhibiting tumor growth by over 90%. In contrast, 10F.9G2 showed only a slight effect on tumor growth, despite targeting the same immune pathway. Initially, the researchers investigated whether differences in how the antibodies bound to target cells or how they moved through the body could explain this disparity. While MIH6 bound more strongly to cancer cells and remained in the bloodstream longer, these differences alone were not enough to account for the drastic differences in treatment outcomes.

Turning to ADCC as a possible explanation, the researchers discovered that 10F.9G2, the one with strong ADCC activity, unexpectedly reduced the number of antitumor immune cells called CD8+ T cells. This happens because PD-L1, the target of these antibodies, is present not only on cancer cells but also on healthy T cells. When antibodies with high ADCC activity bind to PD-L1 on T cells, they inadvertently trigger the destruction of an essential component of the immune system.

This finding reveals that while ADCC is often a desired secondary mechanism for killing cancer cells in ICI therapies, it can cause a detrimental ‘off-target’ effect when targeting immune checkpoint molecules. “Our results highlight the critical need to consider ADCC activity when designing or selecting antibody therapeutics for immune checkpoint blockade, especially in cancer immunotherapy,” says Dr. Tamemoto.

By shedding light on this unwanted side effect, this study could help scientists improve ICI-based therapies through the careful selection of antibody features based on patient characteristics at the molecular level. “If we assess PD-L1 expression on T cells and determine whether anti-PD-L1 monoclonal antibodies with ADCC activity are appropriate in each case, it may be possible to select the optimal antibodies for each patient,” explains Dr. Tamemoto. “By engineering antibodies that avoid damaging essential immune cells, we may be able to minimize side effects and maximize the effectiveness of cancer immunotherapy.”

Further research efforts into these mechanisms may pave the way for improved cancer treatment.

About Assistant Professor Yuta Tamemoto from Chiba University
Dr. Yuta Tamemoto obtained a PhD degree in pharmacy from the Graduate School of Pharmaceutical Sciences at Chiba University in 2023. He currently serves there as Assistant Professor, conducting research on the topics of life sciences and clinical pharmacy, which includes antibody-based therapies, molecular drug interactions, pharmacokinetics, and pharmacodynamics, among others. He currently has eight scientific publications to his name, with more than 30 citations.

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Journal

International Journal of Pharmaceutics

DOI

10.1016/j.ijpharm.2025.125755 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Antibody-dependent cellular cytotoxicity of anti-programmed death-ligand 1 antibodies for T cells attenuate their antitumor efficacy in a murine tumor model

 

Self-disclosure in the era of video communication and embodied virtual reality

Researchers explore the effects of new communication media as well as gender on self-disclosure

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Waseda University

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Researchers find that both the type of communication medium and gender influence self-disclosure.

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Credit: Professor Junko Ichino from Waseda University, Japan

Self-disclosure, or the process of conveying one’s details to others verbally, is crucial for communication. Self-disclosure includes expressing personal information, thoughts, and feelings. It encompasses self-expression and clarification, social validation and control, as well as relationship development, and is closely related to reciprocity, intimacy, trust, interactional enjoyment, and satisfaction.

In recent years, technological advancements have paved the way for new forms of communication, including video-conferencing and embodied virtual reality (VR). It is indispensable to shed light on the phenomenon of self-disclosure in this context to better understand relationship building and mental health.

With this goal, a team of researchers from Japan, led by Professor Junko Ichino from Waseda University (affiliated to Tokyo City University, Japan, at the time of study), including Mr. Masahiro Ide from the Tokyo City University and TIS Inc., Professor Hitomi Yokoyama from Okayama University of Science, Professor Hirotoshi Asano from Kogakuin University, and Professors Hideo Miyachi and Daisuke Okabe from Tokyo City University, has explored the effects of new communication media and gender on self-disclosure. Their findings were published online in Behaviour & Information Technology on June 4, 2025.

Prof. Ichino explains the motivation behind their research, “When I tried accessing VRChat, a social VR platform that gained popularity in Japan around 2017, I was surprised by the lack of polite or superficial conversation and the presence of freedom and directness of communication. I felt that these people would never interact like this in the real world, which led me to become interested in virtual spaces as a place for communication.”

Since self-disclosure is essential for communication, in addition to studies on self-disclosure in face-to-face conversations, there have been many studies on self-disclosure in conversations through text and voice, which are traditional communication media. Many studies have shown that conversations through text and voice encourage self-disclosure more than face-to-face conversations. However, little was known regarding whether new communication media, such as video-conferencing and embodied VR, encourage self-disclosure compared to face-to-face conversations. Therefore, the researchers investigated self-disclosure across four communication media: face-to-face, video, and embodied VR using both realistic and unrealistic avatars. They included 144 participants, aged 20 to 50 years, segregated them into 72 dyads, and encouraged them to develop conversations based on their personal topics. The participants underwent multiple self-disclosure sessions across the four communication media.

The researchers found that embodied VR, especially with unrealistic avatars, resulted in self-disclosure of personal feelings that were 1.5 times higher than in the face-to-face scenario. However, video communication did not differ noticeably from face-to-face. Furthermore, gender pairing also affected self-disclosure. To investigate how gender pairing affects self-disclosure, the researchers classified the participants into female-to-female, male-to-male, male-to-female, and female-to-male. Upon analysis, the team found that female-to-female pairings had the highest degree of self-disclosure, particularly the disclosure of personal information, regardless of the communication medium.

Since embodied VR facilitates self-disclosure of personal feelings compared to face-to-face, the team expects applications in various VR services related to self-expression, including counselling and psychotherapy services, where therapists interact with patients with ailments such as depression, dementia, cancer, adjustment disorders, and anxiety disorders and with clients with various mental symptoms. Moreover, the proposed innovation can lead to novel interventions in caregiver cafés for people who care for elderly people with dementia or who are bedridden, as well as in stress relief services where listening agents listen to people’s worries and anxieties about their physical condition and interpersonal relationships.

Overall, Prof. Ichino envisions a bright future sprouting from their breakthrough findings. “The shift to remote communication using communication media that surged during the COVID-19 pandemic is expected to continue because such media are required to achieve the UN's Sustainable Development Goals. Additionally, the need for mental well-being support, which is closely related to self-disclosure, is expected to increase in the future.”

Together, the insights obtained from this study could be greatly utilised for applications that help in improving mental health.

 

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Reference
Authors: Junko Ichino1, Masahiro Ide2,3, Hitomi Yokoyama4, Hirotoshi Asano5, Hideo Miyachi6, and Daisuke Okabe6     
DOI: 10.1080/0144929X.2025.2507690
Affiliations: 1Faculty of Human Sciences, Waseda University, Saitama, Japan (Affiliation at the time of study: Faculty of Design and Data Science, Tokyo City University, Yokohama, Japan)
2Graduate School of Environmental and Information Studies, Tokyo City University, Yokohama, Japan
3TIS Inc., Tokyo, Japan
4Faculty of Management, Okayama University of Science, Okayama, Japan
5Faculty of Informatics, Kogakuin University, Tokyo, Japan
6Faculty of Informatics, Tokyo City University, Yokohama, Japan

About Waseda University
Located in the heart of Tokyo, Waseda University is a leading private research university that has long been dedicated to academic excellence, innovative research, and civic engagement at both the local and global levels since 1882. The University has produced many changemakers in its history, including eight prime ministers and many leaders in business, science and technology, literature, sports, and film. Waseda has strong collaborations with overseas research institutions and is committed to advancing cutting-edge research and developing leaders who can contribute to the resolution of complex, global social issues. The University has set a target of achieving a zero-carbon campus by 2032, in line with the Sustainable Development Goals (SDGs) adopted by the United Nations in 2015. 

To learn more about Waseda University, visit https://www.waseda.jp/top/en

About Professor Junko Ichino from Waseda University
Joined in 2025, Dr. Junko Ichino is a Professor at the Faculty of Human Sciences, Waseda University, Japan. Prior to this, she served as a Professor at the Faculty of Design and Data Science, Tokyo City University, Yokohama, Japan, from 2017 to 2024. Her research interests include computer-supported cooperative work (CSCW), virtual/augmented reality (VR/AR), human–robot interaction (HRI), interaction with public displays, and computer-supported creative activities. She has published numerous research papers in these fields, which have been cited about 450 times.

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Journal

Behaviour and Information Technology

DOI

10.1080/0144929X.2025.2507690 

Method of Research

Experimental study

Subject of Research

People

Article Title

Effects of new communication media and gender on self-disclosure

 

Nuclear safety: KIT and European Commission conduct joint research

KIT and JRC intensify cooperation and aim to make progress in nuclear applications and their safety

Karlsruher Institut für Technologie (KIT)

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Karlsruhe Institute of Technology (KIT) and the Joint Research Centre (JRC) of the European Commission intend to work together even more closely in the areas of nuclear safety and security as well as nuclear safety monitoring. They want to make an effective contribution to understanding and solving scientific issues – both in fundamental research and in other nuclear applications such as medical research. To this end, the two institutions have signed a new cooperation agreement. The public will benefit from the results.

 

“Nuclear technology continues to play an important role in materials research, healthcare, and energy, to name a few,” says Professor Jan S. Hesthaven, President of KIT. “The cooperation agreement that we have now signed with the JRC helps us secure nuclear safety standards at a high level. At KIT’s nuclear research and education facilities, we will train young researchers who are supposed to guarantee Europe’s future scientific expertise and sovereignty in this field.”

 

“Innovation is a leitmotif for the JRC’s scientific activities, which determines both the scope and the method of research,” says Dr. Ulla Engelmann, Director at the JRC. “Together with KIT, the JRC is pursuing innovative trends and applications emerging in the nuclear sector and is trying to anticipate them. On the other hand, the JRC and KIT are continuously striving to develop and maintain innovative tools and methods to carry out their research.”

 

Responsibility for the Next Generation

The cooperation between KIT and the JRC is aimed primarily at training and further education as well as the development of nuclear capacity in Europe. One of the goals is to establish a dialog between researchers and students. Better mutual access to the nuclear research infrastructures of KIT and the JRC facilitates this for the participating research groups and institutions. Moreover, joint seminars and publications are planned to promote progress in scientific research programs on both sides and to increase their visibility in the relevant scientific and political environments.

 

Strengthening Europe’s Scientific Sovereignty

In addition to preserving scientific expertise in the nuclear field, the aim is for the cooperation to strengthen Europe as a whole in this field. Through joint fundamental research, KIT and the JRC want to expand the understanding of actinide chemistry, i.e. the heavier elements in the periodic table, which are often radioactive. In the field of applied research, the partners want to intensify their cooperation in nuclear medicine, space travel, and intermediate storage and disposal of nuclear waste. They intend to develop innovative strategies for decommissioning and dismantling nuclear facilities and for international nuclear safety surveillance. Another step is to build expertise to better assess reactor safety and structural materials. This includes small modular reactors (SMRs) as well as new materials and manufacturing processes.

 

About the JRC

The Joint Research Centre (JRC) is the European Commission’s science and knowledge service. Its mission is to provide independent, evidence-based research to support the European Commission’s policies and to have a positive impact on society. Through the Directorate for Nuclear Safety and Security, based in Geel (Belgium), Ispra (Italy), Karlsruhe (Germany), and Petten (Netherlands), the JRC conducts research in non-energy applications, nuclear applications, nuclear reactor and fuel safety, disposal of radioactive waste and spent fuel assemblies, nuclear data for reactors, and other applications.

 

More information on the JRC

 

Being “The Research University in the Helmholtz Association”, KIT creates and imparts knowledge for the society and the environment. It is the objective to make significant contributions to the global challenges in the fields of energy, mobility, and information. For this, about 10,000 employees cooperate in a broad range of disciplines in natural sciences, engineering sciences, economics, and the humanities and social sciences. KIT prepares its 22,800 students for responsible tasks in society, industry, and science by offering research-based study programs. Innovation efforts at KIT build a bridge between important scientific findings and their application for the benefit of society, economic prosperity, and the preservation of our natural basis of life. KIT is one of the German universities of excellence.

 

Titanium dioxide particles detected in milk, despite a ban on E171

INRAE - National Research Institute for Agriculture, Food and Environment

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Titanium dioxide (TiO2) has been classified as a possible human carcinogen through inhalation since 2006.1 This nanomaterial was used as a food colouring and opacifying agent (E171) until it was banned for use in food as a precautionary measure in France in 2020[1] and by the European Union in 2022. However, it is still widely used in many everyday products (toothpaste, sunscreen, make-up, medications, plastic, paper, paint, etc.). Previous studies have shown the presence of TiO2 in surface water2 (lakes, rivers, ponds, canals, seas), including sources used for drinking water3 and to fill pools,4 in groundwater,5 in soil6 and in the air.7 The titanium dioxide particles from these sources end up alongside particles released through industrial activity,8 the erosion of building paint and varnishes9 or their use as fertilizers in the form of nanoparticles.10

To better evaluate the impact on living organisms of the widespread presence of titanium dioxide in the environment and measure the real exposure of animals and humans, scientists from INRAE, AP-HP, the SOLEIL Synchrotron and CNRS studied titanium dioxide levels in human and animal milk and in infant formula. Milk serves as a proxy for maternal exposure and is an essential, irreplaceable food that newborns depend on for their healthy development.

Nanoparticles detected in most milk samples

Non-destructive analyses via spectrometry conducted at the SOLEIL Synchrotron and the Lariboisière Hospital AP-HP in Paris were used to describe the titanium particle composition, calculate the total amounts of titanium, detect individual TiO2 particles and determine their size according to the nanometric scale. Size is important because particles smaller than 100 nm are considered nanoparticles and are widely manufactured for their physicochemical properties, which are different than larger particles.

The analysis showed the presence TiO2 nanoparticles in 100% of the animal milk samples (both organic and conventional, in fresh and powdered form, sourced from cows, donkeys and goats) and in 83% of the infant formulas (commercially produced, organic and conventional, for three different age ranges**).

Titanium dioxide passes through the mammary gland

Titanium dioxide particles were detected in human milk taken from 10 volunteers living in or just outside Paris. Rates varied, with some of the women’s samples showing up to 15 times more TiO2 than others. This shows that titanium dioxide can cross the mammary gland barrier.

Using this new analysis technique, 6 million to 3.9 billion TiO2 particles per litre were detected in infant formula, and 16 to 348 million TiO2 particles per litre were detected in animal milk.

Other sources of titanium

This study of contamination in milk reflects the level of exposure in newborns and mothers as well as adult milk drinkers. Previous research led by INRAE had shown that nanoparticles of titanium dioxide consumed through food during pregnancy can cross the placental barrier. This latest study shows that infants’ exposure does not end at birth: titanium particles were detected in milk despite the ban on E171 use in food, which suggests contamination through sources other than food.

Future studies could build on the characterization of titanium particles in milk for this study (size, percentage of particles smaller than 100 nm, type of Ti-bearing minerals, crystalline form) to evaluate the toxicity of combinations of particles identified depending on the species and type of milk.

Upcoming research on women in the Paris region (urban areas known for having higher levels of titanium exposure) will investigate the effects of diet and the use of cosmetics, medications and other titanium-containing products on exposure levels.

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[1] ANSES opinion. Request No. 2019-SA-0036 on the risks associated with ingestion of the food additive E171.

** Stage 1 for infants aged 0 to 6 months (corresponding to “first infant formula”); stage 2 for infants aged 6 to 12 months and stage 3 for toddlers aged 12 to 36 months (corresponding to “follow-on formula”).

Bibliographic references

[1] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Carbon Black, Titanium Dioxide and Non-Asbestiform Talc. IARC monographs on the evaluation of carcinogenic risks to humans, vol. 93, Lyon, International Agency for Research on Cancer (2006)
Commission Delegated Regulation (EU) 2020/217 of 4 October 2019 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures and correcting that Regulation

[2] Andreas Gondikas P., Von Der Kammer F., Bruce Reed R. et al. (2014). Release of TiO2 Nanoparticles from Sunscreens into Surface Waters: A One-Year Survey at the Old Danube Recreational Lake. Environmental Science & Technology, DOI:https://doi.org/10.1021/es405596y
Azimzada A., Ibrahim J., Madjid H. et al. (2021). Quantification and Characterization of Ti-, Ce-, and Ag-Nanoparticles in Global Surface Waters and Precipitation. Environmental Science & Technology, DOI: https://doi.org/10.1021/acs.est.1c00488 
Gonzalez de Vega R., Lockwood T.E., Xu X. et al. (2022). Analysis of Ti- and Pb-based particles in the aqueous environment of Melbourne (Australia) via single particle ICP-MS. Analytical and Bioanalytical Chemistry, DOI: https://doi.org/10.1007/s00216-022-04052-0
Bäuerlein PS., Emke E., Tromp P. et al. (2017). Is there evidence for man-made nanoparticles in the Dutch environment? Science of The Total Environment, DOI : https://doi.org/10.1016/j.scitotenv.2016.09.206
Souza Iara da C., Mendes Victor AS., Duarte ID., et al. (2019). Nanoparticle transport and sequestration: Intracellular titanium dioxide nanoparticles in a neotropical fish. The Science of the Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2018.12.142
Labille J., Slomberg D., Riccardo C. et al. (2020). Assessing UV filter inputs into beach waters during recreational activity: A field study of three French Mediterranean beaches from consumer survey to water analysis. The Science of the Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2019.136010

[3] Bäuerlein PS., Emke E., Tromp P. et al. (2017). Is there evidence for man-made nanoparticles in the Dutch environment? Science of The Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2016.09.206

[4] Holbrook DR., Motabar D., Quiñones O. et al. (2013). Titanium distribution in swimming pool water is dominated by dissolved species. Environmental PollutionI, DOI: https://doi.org/10.1016/j.envpol.2013.05.044

[5] Bäuerlein PS., Emke E., Tromp P. et al. (2017). Is there evidence for man-made nanoparticles in the Dutch environment? Science of The Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2016.09.206

[6] Kim B., Murayama M., Colman BP. et al. (2012). Characterization and environmental implications of nano- and larger TiO2 particles in sewage sludge, and soils amended with sewage sludge. Journal of Environmental Monitoring, DOI: https://doi.org/10.1039/C2EM10809G  
Mitrano DM., Mehrabi K., Dasilva YAR. et al. (2017). Mobility of metallic (nano)particles in leachates from landfills containing waste incineration residues. Environmental Science: Nano, DOI: https://doi.org/10.1039/C6EN00565A

[7] Bäuerlein PS., Emke E., Tromp P. et al. (2017). Is there evidence for man-made nanoparticles in the Dutch environment? Science of The Total Environment, DOI : https://doi.org/10.1016/j.scitotenv.2016.09.206
Souza IDC., Morozesk M., Mansano AS. et al. (2021). Atmospheric particulate matter from an industrial area as a source of metal nanoparticle contamination in aquatic ecosystems. Science of The Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2020.141976
Amato F., Viana M., Richard A. et al. (2011). Size and time-resolved roadside enrichment of atmospheric particulate pollutants. Atmospheric Chemistry and Physics, DOI: https://doi.org/10.5194/acp-11-2917-2011

[8] Souza IDC., Morozesk M., Mansano AS. et al. (2021). Atmospheric particulate matter from an industrial area as a source of metal nanoparticle contamination in aquatic ecosystems. Science of The Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2020.141976

[9] Baalousha M., Yang Y., Vance ME. et al. (2016). Outdoor urban nanomaterials: The emergence of a new, integrated, and critical field of study. Science of The Total Environment, DOI: https://doi.org/10.1016/j.scitotenv.2016.03.132

[10] Rodríguez-González V., Terashima C., Fujishima A. et al. (2019). Applications of photocatalytic titanium dioxide-based nanomaterials in sustainable agriculture. Journal of Photochemistry and Photobiology C: Photochemistry Reviews. DOI: https://doi.org/10.1016/j.jphotochemrev.2019.06.001

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Journal

Science of The Total Environment

DOI

10.1016/j.scitotenv.2025.180040 

Article Title

Detection of titanium dioxide particles in human, animal and infant formula milk

Article Publication Date

23-Jul-2025