Targeting the immune microenvironment for ovarian cancer therapy

Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments

Spatial Profiling of Ovarian Carcinoma and Tumor Microenvironment Evolution under Neoadjuvant Chemotherapy

Ovarian carcinoma; Tumor microenvironment; Neoadjuvant chemotherapyCarcinoma de ovario; Microambiente tumoral; Quimioterapia neoadyuvanteCarcinoma d'ovari; Microambient tumoral; Quimioteràpia neoadjuvantPurpose: This study investigates changes in CD8+ cells, CD8+/Foxp3 ratio, HLA I expression, and immune coregulator density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. Experimental Design: Multiplexed immune profiling and cell clustering analysis were performed on paired matched ovarian cancer samples to characterize the immune tumor microenvironment (iTME) at diagnosis and under NACT in patients enrolled in the CHIVA trial (NCT01583322). Results: Several immune cell (IC) subsets and immune coregulators were quantified pre/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA I+-enriched tumors were associated with a better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance, and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into four subsets: high Binf, enriched in B clusters; high Tinf and low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors were segregated into three clusters: high BinfTinf, low Tinf, and desert. The high BinfTinf, more diverse in IC composition encompassing T, B, and NK cells, correlated with improved survival. PDL1 was rarely expressed, whereas TIM3, LAG3, and IDO1 were more prevalent. Conclusions: Several iTMEs exist during tumor evolution, and the NACT impact on iTME is heterogeneous. Clustering analysis of patients unravels several IC subsets within ovarian cancer and can guide future personalized approaches. Targeting different checkpoints such as TIM3, LAG3, and IDO1, more prevalent than PDL1, could more effectively harness antitumor immunity in this anti-PDL1–resistant malignancy.This work was supported by donations from patients and families through the “Parrainage Cancers Gynécologiques” Program and by the Association de Recherche Cancers Gynécologiques Research

Circulating Tumor DNA from Ascites as an alternative to tumor sampling for genomic profiling in ovarian cancer patients

Abstract Genomic testing is crucial for the management of ovarian cancer. DNA from biopsies at diagnostic laparoscopies or interval debulking surgery after neoadjuvant chemotherapy, has a high failure rate. At relapse, biopsies may not be feasible. The aim of our study was to evaluate the feasibility and usefulness of measuring genomic instability score (GIS) on cell-free DNA (cfDNA) from ascites. Patients enrolled in a prospective study (NCT03010124) consented to analysis of biological samples. CfDNA was extracted from 1 to 4 ml of double-centrifuged fresh ascites. Targeted Next-generation sequencing (NGS) including TP53 mutation (TP53m) was performed on cfDNA to confirm the presence of tumor cfDNA. Single Nucleotide Polymorphism Array estimating somatic copy number alterations (SCNA) was performed to calculate GIS for Homologous-Recombination deficiency (HRD). Twenty nine ascites were collected from 20 patients with suspected or confirmed OC. 93% (27/29) samples had detectable cfDNA (median 1120 ng [24-5732]) even when obtained during chemotherapy. A deleterious mutation was identified in 100%, with high allelic frequencies (median 60% [3.3–87%]), confirming that cfDNA was tumoral. SCNA analyses on 17 patients showed 11 high GIS, and 6 low GIS. 4 patients with confirmed BRCA mutation had a high GIS on ascites. When available from the same patient, SCNA profiles on ascites and tumor were superimposable. Ascites is frequent at diagnosis and relapse and yields large amounts of tumoral cfDNA. SCNA analysis on ascitic cfDNA is feasible and can detect the same HRD scar as tumor testing. Ascites could provide an alternative to tumor sampling for HRD and BRCA testing

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Simple Summary Recently, the introduction of immunotherapy radically changed the therapeutic algorithm of non-small-cell lung cancer as an upfront or secondary strategy. Unfortunately, the small amount of patient benefits from immune-checkpoint inhibitors (ICI) and the prognostic role of concomitant treatments are a burning open issue. The use of steroids was associated with poor outcomes during ICI. We investigated the impact of intercurrent steroids, according to clinical indication, which is actually unclear. Interestingly, the use of intercurrent steroids given for cancer-unrelated symptoms has no survival impact on our study cohort. Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (>= 10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naive at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1-12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p <0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9-1.5] and mOS [1.9 mo.; 95%CI, 1.5-2.4; p <0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2-5.6] and OS [HR 4.53; 95% CI, 1.8-11.1], both p <0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms

Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer

43siAside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.reservedopenDerosa, Lisa; Routy, Bertrand; Thomas, Andrew Maltez; Iebba, Valerio; Zalcman, Gerard; Friard, Sylvie; Mazieres, Julien; Audigier-Valette, Clarisse; Moro-Sibilot, Denis; Goldwasser, François; Silva, Carolina Alves Costa; Terrisse, Safae; Bonvalet, Melodie; Scherpereel, Arnaud; Pegliasco, Hervé; Richard, Corentin; Ghiringhelli, François; Elkrief, Arielle; Desilets, Antoine; Blanc-Durand, Felix; Cumbo, Fabio; Blanco, Aitor; Boidot, Romain; Chevrier, Sandy; Daillère, Romain; Kroemer, Guido; Alla, Laurie; Pons, Nicolas; Le Chatelier, Emmanuelle; Galleron, Nathalie; Roume, Hugo; Dubuisson, Agathe; Bouchard, Nicole; Messaoudene, Meriem; Drubay, Damien; Deutsch, Eric; Barlesi, Fabrice; Planchard, David; Segata, Nicola; Martinez, Stéphanie; Zitvogel, Laurence; Soria, Jean-Charles; Besse, BenjaminDerosa, Lisa; Routy, Bertrand; Thomas, Andrew Maltez; Iebba, Valerio; Zalcman, Gerard; Friard, Sylvie; Mazieres, Julien; Audigier-Valette, Clarisse; Moro-Sibilot, Denis; Goldwasser, François; Silva, Carolina Alves Costa; Terrisse, Safae; Bonvalet, Melodie; Scherpereel, Arnaud; Pegliasco, Hervé; Richard, Corentin; Ghiringhelli, François; Elkrief, Arielle; Desilets, Antoine; Blanc-Durand, Felix; Cumbo, Fabio; Blanco, Aitor; Boidot, Romain; Chevrier, Sandy; Daillère, Romain; Kroemer, Guido; Alla, Laurie; Pons, Nicolas; Le Chatelier, Emmanuelle; Galleron, Nathalie; Roume, Hugo; Dubuisson, Agathe; Bouchard, Nicole; Messaoudene, Meriem; Drubay, Damien; Deutsch, Eric; Barlesi, Fabrice; Planchard, David; Segata, Nicola; Martinez, Stéphanie; Zitvogel, Laurence; Soria, Jean-Charles; Besse, Benjami

Second-line treatment outcomes after progression from first-line chemotherapy plus immunotherapy in patients with advanced non-small cell lung cancer

INTRODUCTION: Chemotherapy plus immunotherapy is the standard of care for patients with metastatic NSCLC. No study has evaluated the outcomes of second-line chemotherapy treatments after progression following first-line chemo-immunotherapy. METHOD: This multicenter retrospective study evaluated the efficacy of second line (2L) chemotherapies after progression under first-line (1L) chemo-immunotherapy, measured by overall survival (2L-OS) and progression free survival (2L-PFS). RESULTS: A total of 124 patients were included. The mean age was 63.1 years, 30.6 % of the patients were female, 72.6 % had an adenocarcinoma and 43.5 % had a poor ECOG-performance status prior to 2L initiation. Sixty-four (52.0 %) patients were considered resistant to first line chemo-immunotherapy. (1L-PFS < 6 months). In 2L treatments, 57 (46.0 %) patients received taxane monotherapy, 25 (20.1 %) taxane plus anti-angiogenic, 12 (9.7 %) platinum-based chemotherapy and 30 (24.2 %) other chemotherapy. At a median follow-up of 8.3 months (95 %CI: 7.2-10.2), post initiation of 2L treatment, the median 2L-OS was 8.1 months (95 % CI: 6.4-12.7) and the median 2L-PFS was 2.9 months (95 %CI: 2.4-3.3). Overall, the 2L-objective response and 2L-disease control rates were 16.0 %, and 42.5 %, respectively. Taxane plus anti-angiogenic and platinum rechallenge achieved longest median 2L-OS: not reached (95 %CI: 5.8-NR) and 17.6 months (95 %CI 11.6-NR), respectively (p = 0.05). Patients resistant to the 1L treatment had inferior outcomes (2L-OS 5.1 months, 2L-PFS 2.3 months) compared with 1L responders (2L-OS 12.7 months, 2L-PFS 3.2 months). CONCLUSION: In this real-life cohort, 2L chemotherapy achieved modest activity following progression under chemo-immunotherapy. 1L-resistant patients remained a refractory population, highlighting a need for new 2L strategies

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non–small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. Patients and methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16low cells (immature) by flow cytometry. Results: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. Conclusion: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non–small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. Patients and methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16low cells (immature) by flow cytometry. Results: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. Conclusion: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance

Therapy Related Myeloid Neoplasms Following PARP Inhibitors : Real-Life Experience

International audienc