British Journal of Cancer

Ciccolini, Joseph; Milano, Gerard

doi: 10.1038/s41416-023-02478-6pmid: 37898723

Brest, Patrick; Mograbi, Baharia; Pagès, Gilles; Hofman, Paul; Milano, Gerard

doi: 10.1038/s41416-023-02437-1pmid: 37735244

The combination of immune checkpoint inhibitors and anti-angiogenic agents is a promising new approach in cancer treatment. Immune checkpoint inhibitors block the signals that help cancer cells evade the immune system, while anti-angiogenic agents target the blood vessels that supply the tumour with nutrients and oxygen, limiting its growth. Importantly, this combination triggers synergistic effects based on molecular and cellular mechanisms, leading to better response rates and longer progression-free survival than treatment alone. However, these combinations can also lead to increased side effects and require close monitoring.

Sicard, G.; Protzenko, D.; Giacometti, S.; Barlési, F.; Ciccolini, J.; Fanciullino, R.

doi: 10.1038/s41416-023-02350-7pmid: 37524968

BackgroundSuccessful immunotherapy is restricted to some cancers only, and combinatorial strategies with other drugs could help to improve their efficacy. Here, we monitor T cells in NSCLC model after treatment with cytotoxics (CT) and anti-VEGF drugs, to understand when immune checkpoint inhibitors should be best associated next.MethodsIn vivo study was performed on BALB/c mice grafted with KLN205 cells. Eight treatments were tested including control, cisplatin and pemetrexed as low (LD CT) and full (MTD CT) dose as single agents, flat dose anti-VEGF and the association anti-VEGF + CT. Full immunomonitoring was performed by flow cytometry on tumor, spleen and blood over 3 weeks.ResultsImmunomodulatory effect was dependent upon both treatments and time. In tumors, combination groups shown numerical lower Treg cells on Day 21. In spleen, anti-VEGF and LD CT group shown higher CD8/Treg ratio on Day 7; on Day 14, higher T CD4 were observed in both combination groups. Finally, in blood, Tregs were lower and CD8/Treg ratio higher, on Day 14 in both combination groups. On Day 21, CD4 and CD8 T cells were higher in the anti-VEGF + MTD CT group.ConclusionsAnti-VEGF associated to CT triggers notable increase in CD8/Tregs ratio. Regarding the scheduling, a two-week delay after using anti-VEGF and CT could be the best sequence to optimize antitumor efficacy.[graphic not available: see fulltext]

Bruno, René; Chanu, Pascal; Kågedal, Matts; Mercier, Francois; Yoshida, Kenta; Guedj, Jérémie; Li, Chunze; Beyer, Ulrich; Jin, Jin Y.

doi: 10.1038/s41416-023-02190-5pmid: 36765177

Longitudinal models of biomarkers such as tumour size dynamics capture treatment efficacy and predict treatment outcome (overall survival) of a variety of anticancer therapies, including chemotherapies, targeted therapies, immunotherapies and their combinations. These pharmacological endpoints like tumour dynamic (tumour growth inhibition) metrics have been proposed as alternative endpoints to complement the classical RECIST endpoints (objective response rate, progression-free survival) to support early decisions both at the study level in drug development as well as at the patients level in personalised therapy with checkpoint inhibitors. This perspective paper presents recent developments and future directions to enable wider and robust use of model-based decision frameworks based on pharmacological endpoints.

Wesevich, Austin; Goldstein, Daniel A.; Paydary, Koosha; Peer, Cody J.; Figg, William D.; Ratain, Mark J.

doi: 10.1038/s41416-023-02367-ypmid: 37542109

Immune checkpoint inhibitors (ICIs) are approved for the treatment of a variety of cancer types. The doses of these drugs, though approved by the Food and Drug Administration (FDA), have never been optimised, likely leading to significantly higher doses than required for optimal efficacy. Dose optimisation would hypothetically decrease the risk, severity, and duration of immune-related adverse events, as well as provide an opportunity to reduce costs through interventional pharmacoeconomic strategies such as off-label dose reductions or less frequent dosing. We summarise existing evidence for ICI dose optimisation to advocate for the role of interventional pharmacoeconomics.

Yang, Zhengyan; Zhu, Jianling; Yang, Tiantian; Tang, Wenjun; Zheng, Xiaowei; Ji, Shaoping; Ren, Zhiguang; Lu, Feng

doi: 10.1038/s41416-023-02379-8pmid: 37543671

BackgroundLong non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified.MethodsWe screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients.ResultsWe observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups.ConclusionsOverall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.

Donini, C.; Galvagno, F.; Rotolo, R.; Massa, A.; Merlini, A.; Scagliotti, G. V.; Novello, S.; Bironzo, P.; Leuci, V.; Sangiolo, D.

doi: 10.1038/s41416-023-02363-2pmid: 37474722

Blocking the inhibitory receptor PD-1 on antitumour T lymphocytes is the main rationale underlying the clinical successes of cancer immunotherapies with checkpoint inhibitor (CI) antibodies (Abs). Besides this main paradigm, there is recent evidence of unconventional and “ectopic” signalling pathways of PD-1, found to be expressed not only by lymphocytes but also by peculiar subsets of cancer cells. Several groups reported on the tumour-intrinsic role of PD-1 in multiple settings, including melanoma, hepatocellular, thyroid, lung, pancreatic and colorectal cancer. Its functional activity appears intriguing but is not yet conclusively clarified. The initial studies are, in fact, supporting either a pro-tumourigenic role involved in chemoresistance and disease relapse or, oppositely, tumour-suppressive functions. The implications connected to the therapeutic administration of PD-1 blocking Abs are, of course, potentially relevant, respectively inferring an anti-tumour activity contrasting PD-1+ tumourigenic cells or a pro-tumoural effect by tackling PD-1 tumour suppressive signalling. The progressive exploration and consideration of this new paradigm of tumour-intrinsic PD-1 signalling may improve the interpretation of the observed clinical effects by anti-PD-1 Abs, likely resulting from multiple cumulative activities, and might provide important bases for dedicated clinical studies that take into account such composite roles of PD-1.[graphic not available: see fulltext]

Parra, Edwin Roger; Ilié, Marius; Wistuba, Ignacio I.; Hofman, Paul

doi: 10.1038/s41416-023-02318-7pmid: 37391504

The past decade has witnessed a revolution in cancer treatment by the shift from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular the immune-checkpoint inhibitors (ICIs). These immunotherapies selectively release the host immune system against the tumour and have shown unprecedented durable remission for patients with cancers that were thought incurable such as advanced non-small cell lung cancer (aNSCLC). The prediction of therapy response is based since the first anti-PD-1/PD-L1 molecules FDA and EMA approvals on the level of PD-L1 tumour cells expression evaluated by immunohistochemistry, and recently more or less on tumour mutation burden in the USA. However, not all aNSCLC patients benefit from immunotherapy equally, since only around 30% of them received ICIs and among them 30% have an initial response to these treatments. Conversely, a few aNSCLC patients could have an efficacy ICIs response despite low PD-L1 tumour cells expression. In this context, there is an urgent need to look for additional robust predictive markers for ICIs efficacy in thoracic oncology. Understanding of the mechanisms that enable cancer cells to adapt to and eventually overcome therapy and identifying such mechanisms can help circumvent resistance and improve treatment. However, more than a unique universal marker, the evaluation of several molecules in the tumour at the same time, particularly by using multiplex immunostaining is a promising open room to optimise the selection of patients who benefit from ICIs. Therefore, urgent further efforts are needed to optimise to individualise immunotherapy based on both patient-specific and tumour-specific characteristics. This review aims to rethink the role of multiplex immunostaining in immuno-thoracic oncology, with the current advantages and limitations in the near-daily practice use.

Dou, Yuqi; Chen, Botian; Yu, Xue; Xin, Qinghua; Ma, Defu

doi: 10.1038/s41416-023-02376-xpmid: 37550527

ObjectivesThis study aims to evaluate the relationship between breast cancer and somatotypes during early life by meta-analysis and give the corresponding advice.MethodsObservational studies till April 5, 2021, which explore women with/without breast cancer who used the Stunkard Figure Rating Scale/Sørensen Somatotypes to evaluate their somatotype before 18 years of age and distant breast cancer risk were included. Using random/fixed-effect models, the pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Then a nonlinear dose–response meta-analysis was conducted using restricted cubic spline analysis.ResultsSix articles involving 15,211 breast cancer patients from 341,905 individuals were included for performing a meta-analysis of early somatotype and breast cancer risk. The pooled results showed that the protection became stronger with the increase of somatotype until it reached 6. The restricted cubic spline model indicated a linear relationship between somatotypes and breast cancer (P-nonlinearity = 0.533). Subgroup analysis of menopausal status showed that increasing somatotype during childhood was increasingly protective against postmenopausal breast cancer from somatotype 3 to somatotype 6, with a 0.887-fold (RR = 0.887, 95% CI: 0.842, 0.934) to 0.759-fold (RR = 0.759, 95% CI: 0.631, 0.913) decreased risk of breast cancer (P-nonlinearity = 0.880), but this association was not found in the population with premenopausal breast cancer (P-nonlinearity = 0.757). When stratified by age, among people younger than 10 years of age, an increase in somatotype was associated with a statistically significant reduction in breast cancer risk. From somatotype 3 to somatotype 6, the risk of breast cancer was reduced by 9.7–27.7% (P-nonlinearity = 0.175).ConclusionsWith early-life adiposity, our data support an inverse association with breast cancer risk, especially age less than 10 years and in postmenopausal women. Since girls with overweight likely remain overweight or even develop obesity in adulthood. While adults with overweight and obese are at increased risk of breast cancer and other types of cancer and various chronic diseases. Hence, we recommend that children should maintain a normal or slightly fat somatotype throughout all periods of life.

Thomas, Elaine M.; Wright, Josephine A.; Blake, Stephen J.; Page, Amanda J.; Worthley, Daniel L.; Woods, Susan L.

doi: 10.1038/s41416-023-02392-xpmid: 37563222

Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.