A Novel Epigenetic Strategy to Concurrently Block Immune Checkpoints PD-1/PD-L1 and CD155/TIGIT in Hepatocellular Carcinoma.

Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.

Immune checkpoint inhibitor-related acquired amegakaryocytosis thrombocytopenia: a case report and literature review.

Introduction: Immune checkpoint inhibitors (ICIs) are used in several advanced malignancies and may cause various immune-related adverse events (irAEs). Among them, hematological irAEs are less described. Acquired amegakaryocytic thrombocytopenia (AAT) is a rare immune hematologic disorder characterized by severe thrombocytopenia and complete absence of megakaryocytes in bone marrow. Case presentation: Herein, we present the case of a patient in their 40s with metastatic melanoma who developed an AAT after 12 cycles of nivolumab (anti-PD1). His platelet count decreased by ≤5 × 109/l without other cytopenia. Bone marrow biopsy showed normal cellularity with a complete absence of megakaryocyte and T-CD8+ lymphocyte infiltration. Given the failure of systemic steroids, eltrombopag was started, an oral thrombopoietin receptor agonist (TPO-RA), and his platelet count subsequently increased with complete response. Discussion: Four other cases are described on literature with the same features than non-ICI-related AAT. All cases occurred after anti-PD/PD-L1 treatment with a median onset of 5 weeks. The presentation of our case is quite different with delayed cytopenia. Both ciclosporin and TPO-RA seem to be efficient therapies. Conclusion: TPO-RA could be preferred in oncologic patients, but safety data are still missing to define clear guidelines for immune-related AAT management.

The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications.

The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N 6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.

Corrigendum: PD-1/PD-L1 immune checkpoint therapy demonstrates favorable safety profile in patients with autoimmune and cholestatic liver disease.

[This corrects the article DOI: 10.3389/fimmu.2023.1326078.].

A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance.

The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance). Here, we review the current FDA-approved ICI for the treatment of certain solid malignancies, evaluate the contrasting responses to checkpoint blockade in different cancer types, explore the known mechanisms associated with checkpoint blockade resistance (CBR), and assess current strategies in the field that seek to overcome these mechanisms. In order to improve current therapies and develop new ones, the immunotherapy field still has an unmet need in identifying other molecules that act as immune checkpoints, and uncovering other mechanisms that promote CBR.

An analysis pipeline for understanding 6-thioguanine effects on a mouse tumour genome.

Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.

Whole-body bioluminescence imaging of T-cell response in PDAC models.

Introduction: The location of T-cells during tumor progression and treatment provides crucial information in predicting the response in vivo. Methods: Here, we investigated, using our bioluminescent, dual color, T-cell reporter mouse, termed TbiLuc, T-cell location and function during murine PDAC tumor growth and checkpoint blockade treatment with anti-PD-1 and anti-CTLA-4. Using this model, we could visualize T-cell location and function in the tumor and the surrounding tumor microenvironment longitudinally. We used murine PDAC clones that formed in vivo tumors with either high T-cell infiltration (immunologically 'hot') or low T-cell infiltration (immunologically 'cold'). Results: Differences in total T-cell bioluminescence could be seen between the 'hot' and 'cold' tumors in the TbiLuc mice. During checkpoint blockade treatment we could see in the tumor-draining lymph nodes an increase in bioluminescence on day 7 after treatment. Conclusions: In the current work, we showed that the TbiLuc mice can be used to monitor T-cell location and function during tumor growth and treatment.

Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. METHODS: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. RESULTS: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression. CONCLUSION: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.

Immune-related thyroid dysfunction is associated with improved long-term prognosis in patients with non-small cell lung cancer treated with immunotherapy: a systematic review and meta-analysis.

Background: Immunotherapy has changed the treatment landscape of lung cancer (LC), but its prognosis is still poor. Whether immunorelated thyroid dysfunction associated with the prognosis of LC patients remains controversial. We aimed to summarize the scientific evidence on whether thyroid dysfunction associated with immunotherapy for LC has a beneficial outcome on the survival of LC patients. Methods: We searched the databases of MEDLINE and Embase for articles published until 31 December 2021 that quantified the impact on non-small cell lung cancer (NSCLC) patients' survival of immune-related thyroid dysfunction. Study-specific data were pooled into hazard ratio (HR) and corresponding 95% confidence intervals (CIs) using random effect models of meta-analysis. Meta-analysis was used to evaluate the relationship between immune-associated thyroid dysfunction and prognosis. Results: A total of 11 articles published between 2015 and 2021 were included, which encompassed a total of over 1,962 NSCLC patients. The studies differed in terms of design, patient characteristics, treatment received, rate/time to immunotherapy-related thyroid dysfunction, and duration of follow-up. But after immunotherapy, we extract survival data. Patients with immunotherapy-associated thyroid dysfunction had better progression-free survival (PFS) (HR 0.54, 95% CI: 0.44-0.64) and overall survival (OS) rate (HR 0.34, 95% CI: 0.25-0.44). Conclusions: Thyroid dysfunction associated with immunotherapy is common and associated with a good prognosis. It can be used as a biological indicator of good prognosis of immunotherapy.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations.

Background: Despite immune checkpoint inhibitors (ICI) being widely used to treat patients with advanced non-small cell lung cancer (NSCLC), few studies examine the role of ICI in patients with proto-oncogene B-Raf, serine/threonine kinase (BRAF) mutations. Methods: A retrospective study was conducted for patients with BRAF-mutant NSCLC who received treatment at Shanghai Pulmonary Hospital between 2014 and 2022. Primary end point was progression-free survival (PFS). Secondary end point was best response (RECIST, version 1.1). Results: The study involved a total of 34 patients with 54 treatments recorded. The median PFS for the whole cohort was 5.8 months and the overall objective response rate (ORR) was 24%. Patients who were treated with ICI combined with chemotherapy reported a median PFS of 12.6 months and an ORR of 44%. Those who were treated with non-ICI therapy came with a median PFS of 5.3 months and an ORR of 14%. Specifically, patients had better clinical benefits with first-line ICI-combined therapy. The PFS was 18.5 months whereas that of non-ICI group was 4.1 months. The ORR was 56% in ICI-combined group and 10% in non-ICI cohort. Conclusions: The findings observed an evidential and significant susceptibility to ICIs combined therapy in patients with BRAF-mutant NSCLC, especially in first-line treatment.

PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis.

Background: Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC. Materials and methods: PubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis. Results: In total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively. Conclusions: PD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.

Immune checkpoint inhibitors related respiratory disorders in patients with lung cancer: A meta-analysis of randomized controlled trials.

Background: In recent years, immune checkpoint inhibitors (ICIs) had extremely rapid growth in anti-cancer and improved outcomes of many malignancies, specifically lung cancer. However, the incidence of ICIs-related adverse events also raised. Using this meta-analysis, ICIs-related respiratory disorders were investigated in lung cancer patients. Methods: Using Cochrane Library, Embase, and PubMed databases, we performed an integrated search for randomized controlled trials (RCTs) to compare respiratory disorders among different regimens. The data was prepared with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline, and the quality of included studies was evaluated based on the Cochrane manual. Results: In total, 22 RCTs were involved in this meta-analysis. Compared with ICIs, chemotherapy reduced the risk of interstitial lung disease (p = 0.03; SMD: 2.81; 95% CI: 1.08, 7.27), pleural effusion (p = 0.002; SMD: 2.12; 95% CI: 1.32, 3.42), and pneumonitis (p < 0.00001; SMD: 9.23; 95% CI: 4.57, 18.64). ICIs plus chemotherapy could provide a higher probability for patients to suffer pneumonitis than chemotherapy (p = 0.01; SMD: 1.96; 95% CI: 1.17, 3.28). In addition, single ICI brought a lower likelihood for patients suffering pneumonitis than double ICIs (p = 0.004; SMD: 2.17; 95% CI: 1.27, 3.69). Conclusion: ICIs-based treatment, such as ICIs alone, ICIs plus chemotherapy and double ICIs, can raise the incidences of some respiratory disorders in patients with lung cancer. It suggests that ICIs should be conducted based on a comprehensive consideration to prevent ICIs-related respiratory disorders. To a certain degree, this study might be provided to the clinician as a reference for ICIs practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022378901, identifier (CRD42022378901).

A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from the cells of myeloid lineage and is the most frequent leukemia type in adulthood accounting for about 80% of all cases. The most common treatment strategy for the treatment of AML includes chemotherapy, in rare cases radiotherapy and stem cell and bone marrow transplantation are considered. Immune checkpoint proteins involve in the negative regulation of immune cells, leading to an escape from immune surveillance, in turn, causing failure of tumor cell elimination. Immune checkpoint inhibitors (ICIs) target the negative regulation of the immune cells and support the immune system in terms of anti-tumor immunity. Bone marrow microenvironment (BMM) bears various blood cell lineages and the interactions between these lineages and the noncellular components of BMM are considered important for AML development and progression. Administration of ICIs for the AML treatment may be a promising option by regulating BMM. In this review, we summarize the current treatment options in AML treatment and discuss the possible application of ICIs in AML treatment from the perspective of the regulation of BMM.

Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage IIIB-IV non-small cell lung cancer.

Objectives: Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. Methods: The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. Results: A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. Conclusion: Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma.

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma.

Background: Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic cutaneous melanoma (mCM) patients, but their efficacy in young adults aged less than 40 years remains unclear. Materials and methods: We retrospectively analyzed 303 stage IV melanoma patients of different ages treated with nivolumab, pembrolizumab, or ipilimumab plus nivolumab combination therapy. Clinical data and blood values such as LDH, CRP, and absolute immune cell counts were retrieved from the medical records. Pre-treatment serum concentrations of soluble immune checkpoint proteins were measured using ELISA. In addition, information on frequencies of various T cell subsets in the peripheral blood was collected from a previously reported study (ELEKTRA). Patient characteristics and clinical information was correlated with PFS and OS using univariate and multivariate cox regression analysis. Results: Of 303 patients, 33 (11%) were ≤ 40 years old. The older patients had a median age of 64 (95% CI: 61-66). Concerning prognostic parameters, there was no difference between the age groups, e.g., in gender, LDH, or the existence of brain or liver metastases. Patients aged ≤ 40 years [p = 0.014; HR: 1.6 (95% CI: 1.1-2.4)], presence of liver metastases [p = 0.016; HR: 1.4 (95% CI: 1.0-1.9)], line of ICI treatment [p = 0.009; HR: 1.4 (1.0-1.9)], elevated LDH [p = 0.076; HR: 1.3 (95% CI: 0.97-1.8)], and brain metastasis [p = 0.080; HR: 1.3 (95% CI: 0.97-1.7)], were associated with shorter PFS in univariate analysis. Multivariate analysis revealed that the patient's age (≤ 40 years) remains a high-risk factor upon adjusting for all potential confounders [p = 0.067; HR: 1.5 (95% CI: 0.97-2.3)]. Blood parameters revealed that patients ≤ 40 years have relatively higher frequencies of activated CD4 T cells (CD4 + Ki67 + CD4 + ICOS +) in the blood, and significantly lower number of basophils and CD45RA- memory T cells, compared to patients above 40 years (p < 0.05). In addition, patients ≤ 40 years experiencing disease progression within 6 months of ICI treatment had increased concentrations of sPDL1 (p = 0.05) and sTIM3 (p = 0.054) at baseline. Conclusion: Young patients with stage IV melanoma may experience shorter progression-free survival upon ICI treatment compared to patients above 40 years and are characterized by fewer basophils and memory T cells in the blood.