Nice "aperitivo" from Pr. Alberto Mantovani. He highlighted the link between inflammation, macrophages and tumor development, as well as the central role of complement (lectin pathway) and IL1 receptors in angiogenesis and tumor invasiveness . Moreover, he noted that the majority of MSA4 macrophage proteins had as yet unknown functions! What an avenue on research!

We continued with Prof. Antoine Italiano, who highlighted the crucial role that tertiary lymphoid structures could play in the treatment of soft-tissue sarcoma . In particular, it was highlighted that the presence of these structures in patients could represent a positive prognostic factor for PD-1 blockade-based therapies , opening up new prospects for personalizing the treatment of these cancers by immunotherapy.

Then, inspiring presentation by Prof. Guido Kroemer on the effect of Bci-2 inhibitors (venetoclax and navitoclax), which among other things 1) enhance DC function on target 2) activate CGAS sting IRF3 pathway 3) autophagy .... Thus, therapeutical vaccination  with Bcm-2 increase PD1 blockade and show very promising results on tumor control.

To close this session, Prof. Silvia Formenti stressed the importance of analyzing recent negative results obtained in various prospective randomized trials combining radiotherapy and immunotherapy. This could help optimize   the parameters of such combinations, such as their scheduling, radiotherapy dose, the various effects outside the irradiation field, or even the choice of whether or not to irradiate tumor-draining lymph nodes.

A very enlightening  presentation by Jordi Remon-Masip on the conclusions and opportunities of the PACIFIC trial, which marked a major change for NSCLC cancers. Several clinical trials have since built on these results, such as the COAST trial or the BTCRC-LUN trial. The latter was particularly conclusive, with only 6 months of consolidation immunotherapy, compared with 1 year previously. What's more, new-generation of trials will have to include patient-specific dose customization, using new RT techniques (proton, FLASH).

In the second presentation, Kevin Harrington highlighted the promising potential of DNA damage  repair inhibitors in combination with radiotherapy. More specifically, the combination of ATR inhibitors with radiotherapy seems capable of reshaping the tumor immune infiltrate and of favoring their expression of immunosuppressive markers . This highlights the potential of such combinations to synergize with immune checkpoint inhibitor combinations, following appropriate treatment scheduling.

1.        Then, an extremely interesting presentation by Dr Lorenzo Galluzzi about Immunological Cell Death (ICD) . He presented the different ingredients needed to obtain an ICD: a clever mix  of RCD, antigenicity, adjuventicity and microenvironment. These elements can be induced by different ICD inducers such as radiation, infectious pathogens, imunogenic chemotherapy ... Now, the burning question  is : Is abscopal response a pure consequence of ICD? In any case, ICD seems to be a pivotal parameter in the design of future RT/IO combinations.

The final presentation of the day was an opportunity for Prof. Fabrice André to outline the new perspectives  associated with the use of precision medicine in cancer. In particular, he emphasized the importance of developing simple but innovative tools (e.g., AI) that could be used to predict  the outcome of disease/treatment related toxicities in patients according to their status, based on certain markers. Using the SAFIR02-BREAST study as an example, he underlined the importance of using genomics within the right framework to select the right treatment for each patient.

This opens up new perspectives
in terms of classifying cancers, for example according to the treatments to which they can respond, rather than according to their organ of origin.

Winner of the ImmunoRad Scientific Poster Award
Congratulations Morgane COGELS,
Institut Jules Bordet, Université Libre de Bruxelles (ULB)

To kick off the day , Dr. Claus Sørensen highlighted the ability of cell cycle-regulating signaling pathways to promote cancer cell survival under genotoxic stress. In particular, his work explored the capacity of the combined inhibition of WEE1 and PKMYT1 kinases (which are involved in the inhibition of Cdk activity) to specifically and synergistically induce cancer cell death, featuring a cGAS-STING response, and suggests that these effects could be explored in combination with radiotherapy.

They have also explored how inhibition of the CAD/ICAD pathway can force cancer cells into mitosis, making it an interesting therapeutic target in the context of radiotherapy .

Dr. Floris Foijer then gave a rich presentation on Chromosome instability (CIN) , which leads to aneuploidy and growth delay. Thus, even CIN is a poor driver of cancer, a single mutation convert aneuploid cell into cancer cell! He revealed that gene Stat 1 is the most significant CIN factor, and the more frequently inactivated in aneuploid cancer in TGCA cancer. In particular, the links between cGAS-STING pathway, IL-6 and CIN open up oportnutié  for new therapeutic strategy to elmitae CIN+ cancer.

To round off this session, Prof. Sandra Demaria presented some very inspiring work highlighting  that altered R-loop homeostasis could play a role in the ability of irradiated tumor cells to develop an immunogenic response via the type I IFN pathway. This would notably involve the transfer of exosomes containing RNA:DNA  hybrids from irradiated cancer cells to dendritic cells, notably mediated by depletion of RNAsesH2a/RNAsesH1

Great presentation by Dr Mikael Pittet on myeloid cells in cancer. In addition their role in lymph nodes, tumor inflitrating DC are essential for tumor control and are "the shepherds  of T cells in the microenvironment". Then, an emphasis was made on macrophages, witch are central in term of prognostic information for HNSCC patients.
 In addition, studying the polarity of these macrophages, using patient-based analysis , can provide information about other cell subpopulations.

A brilliant talk by Etienne Meylan on tumor associated neutrophils (TANs), which can be pro- or anti-tumor  depending on their polarization. In particular, he revealed that TANs in tumors could exhibit aberrantly long lifespans compared with other compartments, and that it's as they age that TANs become pro-tumoral. He then identified Bcl-xL as a biomarker of TANs aging, whose blockade diminishes TANs aging at short term and delaying tumor growth at longer term (2 - 3 weeks). This could be an important step towards targeting TANs in a clinical context.

Insightful presentation by Pr Julien Sage who focused on the CD47 marker, a "don't eat-me signal"  which blocks phagocytosis of cancer cells. He revealed that the combination of anti-CD47 with radiotherapy in murine models of SCLC, but also in many other models such as liver metastases, induced a systemic abscopal effect on a non-irradiated tumor, mediated by macrophages ! What a great advance  in the understanding of the abscopal effect!

Following on from the previous presentation, Dr Rodney Cheng-En Hsieh showed that CD47 and PD-L1 were highly expressed on CRC cells and even upregulated by RT in a dose-dependent manner. He confirmed that blocking CD47 could help activating the abcopal effect. Numerous phase I and II clinical trials on CD47 blockade are underway , but none on combination with RT!

Very interesting  presentation by Dr Cristian Fernandez-Palomo on Spatially fractionated radiiation therapy (SBRT), and in particular on microbeam irradiation, which consists in using micrometric irradiation beams depositing dose peaks of several hundred of Gray to the tumor. He has shown that these microbeam irradiations can spare healthy tissue (lower lung fibrosis), induce immune modulation (modulate cytokine release, increase TAN and activated T cells ...) which ultimately leads to better tumor control. Combined with FLASH dose rate, these results are extremely promising !

This opens up new perspectives
in terms of classifying cancers, for example according to the treatments to which they can respond, rather than according to their organ of origin.

Dr Stefan Eichmuller then presented interesting data illustrating the impact of carbon-based radiotherapy on the tumor immune microenvironment. In particular, it was noted that this type of radiotherapy induced an increase in the number of TAMs and NK cells in the irradiation field . Interestingly, it was observed that the absence of immunotherapy (e.g., CTLA4 blockade) induced an increase in the number of naive T cells in tumors outside the irradiation field, while the presence of anti-CTLA4 favored the infiltration of activated T cells. These phenomena could go some way to explaining the long-term protection of the mice cured in this study, which also suggested that the use of anti-CTLA4, rather than anti-PD-L1, would present a better antitumor effect in combination with carbon-based radiotherapy in these conditions.

Very comprehensive presentation by Dr Jean-Pierre Pouget on the theranostic approach of targeted alpha therapy , which is characterized by low dose rate irradiation, very heterogeneous dose distribution and high LET particle. In particular, he pointed out that the low dose rate slightly reduced tumor control, but simultaneously greatly improved the effect on healthy tissue. He then revealed that alpha TRT generated the formation of large ceramide-enriched lipid raft platforms, which triggered signaling pathways that engender cell death. He also discussed in detail the role of extracellular vesicles, which can mediate radiation-induced bystander immunity.

At the end of the session, Prof. Matthias Guckenberger provided interesting insights about the treatment of oligometastatic cancers (3-5 lesions), which could represent a significant proportion of metastatic cancers . Patients with such features could be candidates for treatments optimized according to the lesions treated. Finally, he pointed out that such optimizations could open up opportunities for long term disease-free intervals, but also for overcoming initial/acquired drug resistance, or delaying the initiation of systemic therapies.

Great presentation by Dr Florian Greten on the interaction of IL-1 and Cancer Associated Fibroblast (CAF) in rectal cancer. He presented numerous results on the effect of irradiation and IL-1A on CAF polarization. The results of the Phase I study are extremely promising, and could mark a major advance for patients !

This was followed by an inspiring talk by Prof. Jim Welsh, who highlighted the interesting role of using low doses in combination with high doses of radiotherapy (Radscopal). This technique could represent an interesting alternative, particularly for patients resistant to ICIs, thanks to its ability to reduce the immunosuppressive characteristics of the tumor microenvironment.

 In particular, the use of AI and PET imaging  could help predict patient responses to the Radscopal technique, with the aim of selecting patients eligible for treatments involving the latter in the future. Lastly, innovative prospects involving the use of nanoparticles in combination with the Radscopal technique were mentioned.

Fantastic  presentation by Prof. Ralph Weichselbaum, who painted a picture of the challenges posed by immune response in the irradiated tumor! In particular, he highlighted the role of MDSCs and their link with YTHDF2, whose action is thought to be mediated by a TNFalpha pathway.

The session on tumor microenvironment begins with Prof. Sotiriou's keynote presentation on the final day of ImmunoRad. He focused on the distinct tumor organizations and cellular compositions of triple-negative breast cancer, which can present major heterogeneities within the patient  .He presented work on the use of tertiary lymphoid structures for the prognosis and response to immunotherapy. Finally, he explained that the complexity of the tumor microenvironment in triple-negative breast cancer can be summarized by 9 "ecotypes", which may be linked to survival and could be used as potential therapeutic targets.

Dr Galon then gave an exciting presentation on the use of the immunoscore (ISb) in the context of rectal cancer. He demonstrated that ISb, which represents the immune status of the tumor, can be used to predict not only response to neo-adjuvant chemo-radiotherapy, but also correlates with recurrence-free cancer. He stressed that ISb is of major interest for precision medicine , as it could "guide surgery", recommending a strategy of watch and wait, without surgery, which would be much more comfortable for the patient and avoid side effects.

To conclude this session, Dr Herrera gave an inspiring presentation on the use of low-dose radiotherapy. She began with the example of ovarian cancer, which in 70% of cases does not respond to immune checkpoint inhibitors. She presented the RACIM process (low-dose  radiotherapy and immunotherapy), which enables cold ovarian tumors to be reprogrammed into infiltrated tumors. Using preclinical models, she showed that low-dose irradiation increases polyfunctional T cells, paving the way for the combination of immunotherapy and radiotherapy.

Very insightful talk from Pr Philippe Lambin divided into 2 parts. He first presented the evolution of radiomics methods, from handcrafted radiomics to deep learning . He insisted on the fact that many articles presented positive results, but often used different radiomics signatures, and that we now need to focus on prospective clinical studies. The second part was devoted to "lymphocyte sparing radiotherapy" , in particular the importance of an intact tumor-lymphatic axis for ICI efficacy. Thus, he presented pre-clinical results on the synergy with ICI of different particles types.

Then, great talk by Dr Désirée Deandreis about predictive and prognostic role of PET in immunotherapy. She stressed the need to use multi-lesion and multi-parametric radiomics to deploy their full predictive potential. In addition, she presented advances in predicting response or absocal effect from imaging, notably via immunoPET techniques based on PD1 or CD8 markers. 

Finally, a fascinating presentation by Prof. Eric Deutsch in which he stressed the importance of a PAN-lesion radiomics to obtain solid results, and require new sofware to extract all the radiomics feture of al the lesions to lead to ultra precision radio immunotherapy. He then presented a global strategy to improve RT/IC synergy , notably based on low-dose irradiation of abdomen and mitigation of radio-induced lymphopenia. 

Dr Vanpouille-Box gave an interesting and comprehensive presentation on the regulation of fatty acid metabolism in the context of glioblastoma (GBM). She began by showing that in vitro , radiotherapy disrupts GBM metabolism and promotes the production of unsaturated acids. She pointed out that while fatty acid synthase inhibitors (FASNi) combined with radiotherapy do not improve overall survival, anti-PD1 combined with radiotherapy increases survival in irradiated GBM .

An enlightening presentation by Pr Stephane Depil on HERV (Human endogenous retroviruses). He reminded us that the response to HERV is poorly characterized, and presented multiple ex vivo results demonstrating the immunogenicity and capacity of HERV to generate anti-tumor CD8 T lymphocytes . He concluded his presentation with one extremely encouraging pre-clinical in vivo result !

This opens up new perspectives
in terms of classifying cancers, for example according to the treatments to which they can respond, rather than according to their organ of origin.

Prof. Karam then gave a stimulating presentation, focusing on the use of radiotherapy to target interleukin 2 (IL2) to trigger systemic immunity, using pancreatic adenocarcinoma as a scaffold. She presented a phase 1 trial involving 24 patients and retrospective data. She highlighted that radiotherapy with PD1-IL2v increases  activation, polyfunctionality and stemness of CD8+ T cells, while reducing depletion. In a preclinical model , she demonstrated that it also increased cell circulation after tumor eradication.

This opens up new perspectives
in terms of classifying cancers, for example according to the treatments to which they can respond, rather than according to their organ of origin.

Finally, Prof. Laurence Zitvogel presented a remarkable work on the role of the gut microbiota in cancer , which is gaining increasing interest within the community. In particular, she revealed the deleterious effect of antibiotics on the microbiota, as well as the role of MAdCAM-1, the first identified gut immune checkpoint for cancer immunosuveillance. She then highlighted  that off target intestinal low dose irradiation to abdomen was associated with “better” gut microbia and lead to long term benefits. Finally, she presented TOPOSCORE, a simple PCR-based assesment to predict OS of NSCLC patients based on microbia quality.

1 In the final session, Dr. Romano gave a highly informative and clinical presentation of the results of a Phase 1 clinical trial (NICOL). The subject was the use of Nivolumab and chemoradiotherapy in cervical cancer. She first confirmed the value of such a treatment and recommended a phase 2 trial . Indeed, she showed that hypotension and acute renal failure were not linked to Nivolumab but to cisplatin administration . She pointed out that PD-L1 expression on tumor cells does not appear to enrich the response to PD-1 blockade.

Then, an incredible presentation by Dr Michele Mondini on partial tumor irradiation combining low dose (LD) RT and High Dose (HD) RT. In particular, he showed in mice that this strategy improves tumor control and survival , increases the proportion of effector CD8 T cells and, when blocking CXCR2, improves tumor volume control by reducing infiltration of immunosuppressive neutrophiles. He concluded with the potential clinical implications of their results! What a promising work !

To conclude the conference, Prof. Hüber presented an overview of the impact of photon and particle radiation on the innate immune response. He began his presentation by explaining that the main obstacle to immunotherapy is the poor infiltration of immune cells into tumors . Based on the results of a phase 2 clinical trial involving 66 patients, he showed that natural killer (NK) cells accumulate in irradiated tumors and, when combined with CXCL8, are associated with increased overall survival. He concluded that photons, protons and carbons have a fairly similar immune effect.