Quantitative assessment of Siglec-15 expression in lung, breast, head, and neck squamous cell carcinoma and bladder cancer.

Immune checkpoint blockade with programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has resulted in significant progress in the treatment of various cancer types. However, not all patients respond to PD-1/PD-L1 blockade, underscoring the importance of identifying new potential targets for immunotherapy. One promising target is the immune system modulator Siglec-15. In this study, we assess Siglec-15 expression in solid tumors, with a focus on lung, breast, head and neck squamous and bladder cancers. Using quantitative immunofluorescence (QIF) with a previously validated antibody, we found increased Siglec-15 expression in both tumor and immune cells in all the four cancer types. Siglec-15 was seen to be predominantly expressed by the stromal immune cells (83% in lung, 70.1% in breast, 95.2% in head and neck squamous cell and 89% in bladder cancers). Considerable intra-tumoral heterogeneity was noted across cancer types. As previously described for non-small cell lung cancer (NSCLC), Siglec-15 expression was seen to be mutually exclusive to PD-L1 in all the four cancer types, although this differential expression was maintained but somewhat diminished in head and neck squamous cell carcinoma (HNSCC). Siglec-15 was not prognostic either for overall survival (OS) or progression-free survival (PFS). In summary, we show broad expression of this potential immune modulatory target in a wide range of cancer types. These data suggest potential future clinical trials in these tumor types.

Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case-control study.

PURPOSE: Triple negative breast cancer (TNBC) is more common in African American (AA) than Non-AA (NAA) population. We hypothesize that tumor microenvironment (TME) contributes to this disparity. Here, we use multiplex quantitative immunofluorescence to characterize the expression of immunologic biomarkers in the TME in both populations. PATIENTS AND METHODS: TNBC tumor resection specimen tissues from a 100-patient case: control cohort including 49 AA and 51 NAA were collected. TME markers including CD45, CD14, CD68, CD206, CD4, CD8, CD20, CD3, Ki67, GzB, Thy1, FAP, aSMA, CD34, Col4, VWF and PD-L1 we quantitatively assessed in every field of view. Mean expression levels were compared between cases and controls. RESULTS: Although no significant differences were detected in individual lymphoid and myeloid markers, we found that infiltration with CD45+ immune cells (p = 0.0102) was higher in TNBC in AA population. AA TNBC tumors also had significantly higher level of lymphocytic infiltration defined as CD45+ CD14- cells (p = 0.0081). CD3+ T-cells in AA tumors expressed significantly higher levels of Ki67 (0.0066) compared to NAAs, indicating that a higher percentage of AA tumors contained activated T-cells. All other biomarkers showed no significant differences between the AA and NAA group. CONCLUSIONS: While the TME in TNBC is rich in immune cells in both racial groups, there is a numerical increase in lymphoid infiltration in AA compared to NAA TNBC. Significantly, higher activated T cells seen in AA patients raises the possibility that there may be a subset of AA patients with improved response to immunotherapy.

Tumor Dormancy: Implications for Invasion and Metastasis.

Tumor dormancy refers to a critical stage of cancer development when tumor cells are present, but cancer does not progress. It includes both the concept of cellular dormancy, indicating the reversible switch of a cancer cell to a quiescent state, and that of tumor mass dormancy, indicating the presence of neoplastic masses that have reached cell population equilibrium via balanced growth/apoptosis rates. Tumor dormancy provides the conceptual framework, potentially explaining a major challenge in clinical oncology, tumor recurrence, which may occur years after cancer diagnosis. The mechanisms by which tumors are kept dormant, and what triggers their reawakening, are fundamental questions in cancer biology. It seems that a plethora of intracellular pathways and extracellular factors are involved in this process, rewiring the cells to plastically alter their metabolic and proliferative status. This phenomenon is highly dynamic in space and time. Mechanistic insights into both cellular and tumor dormancy have provided the rationale for targeting this otherwise stable period of cancer development, in order to prevent recurrence and maximize therapeutic benefit.

Programmed Death-Ligand 1 as a Regulator of Tumor Progression and Metastasis.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has long been implicated in modeling antitumor immunity; PD-1/PD-L1 axis inhibitors exert their antitumor effects by relieving PD-L1-mediated suppression on tumor-infiltrating T lymphocytes. However, recent studies have unveiled a distinct, tumor-intrinsic, potential role for PD-L1. In this review, we focus on tumor-intrinsic PD-L1 signaling and delve into preclinical evidence linking PD-L1 protein expression with features of epithelial-to-mesenchymal transition program, cancer stemness and known oncogenic pathways. We further summarize data from studies supporting the prognostic significance of PD-L1 in different tumor types. We show that PD-L1 may indeed have oncogenic potential and act as a regulator of tumor progression and metastasis.

Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer.

Although smoking is the primary cause of lung cancer, only about 15% of lifelong smokers develop the disease. Moreover, a substantial proportion of lung cancer cases occur in never-smokers, highlighting the potential role of inherited genetic factors in the cause of lung cancer. Lung cancer is significantly more common among those with a positive family history, especially for early-onset disease. Therefore, the presence of pathogenic germline variants might act synergistically with environmental factors. The incorporation of next-generation sequencing in routine clinical practice has led to the identification of cancer-predisposing mutations in an increasing proportion of patients with lung cancer. This Review summarises the landscape of germline susceptibility in lung cancer and highlights the importance of germline testing in patients diagnosed with the disease, which has the potential to identify individuals at risk, with implications for tailored therapeutic approaches and successful prevention through genetic counselling and screening.

Efficacy and Safety of Tinzaparin Thromboprophylaxis in Lung Cancer Patients with High Thromboembolic Risk: A Prospective, Observational, Single-Center Cohort Study.

BACKGROUND: The aim of this study was to record and assess the efficacy and safety ofthromboprophylaxis with an intermediate dose of Tinzaparin in lung cancer patients with high thrombotic risk. METHODS: This was a non-interventional, single-arm, prospective cohort study of lung cancer patients who received thromboprophylaxis with Tinzaparin 10.000 Anti-Xa IU in 0.5 mL, OD, used in current clinical practice. Enrolled ambulatory patients signed informed consent. Anti-Xa levels were tested. RESULTS: In total, 140 patients were included in the study, of which 81.4% were males. The histology of the tumor was mainly adenocarcinoma. Lung cancer patients with high thrombotic risk based on tumor, patient, treatment, and laboratory-related factors were enrolled. Only one patient experienced a thrombotic event (0.7%), and 10 patients had bleeding events (7.1%), including only one major event. Anti-Xa levels measured at 10 days and 3 months did not differ significantly between patients who developed hemorrhagic events and those who did not (p = 0.26 and p = 0.32, respectively). CONCLUSION: Thromboprophylaxis with an intermediate Tinzaparin dose in high thrombotic-risk lung cancer patients is a safe and effective choice for the prevention of VTE.

Endocrine Immune-Related Adverse Events Are Independent Predictors of Survival in Patients with Lung Cancer.

Lung cancer (LC) is a serious health problem worldwide. Survival outcomes have improved over time due to the widespread use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs). Endocrine immune-related adverse events (e-irAEs) are common in LC patients treated with ICIs. We performed a retrospective study of patients with LC who received treatment with ICIs at a tertiary referral center between January 2014 and October 2023. In total, 983 LC patients were included in the study. E-irAEs presented at a median time of 4.1 months and included hypothyroidism (15.6%), hyperthyroidism (4.3%), adrenal insufficiency (0.4%), hypophysitis (0.4%), and diabetes mellitus (0.2%). These toxicities were not related to the duration of treatment or the type of ICIs. Most (97.6%) e-irAEs were mild (grade 1-2). Median overall survival (OS) was higher in LC patients who experienced e-irAEs (31.6 months) compared to those who did not (10.8 months). The difference remained statistically significant in the 3-month (HR: 0.42) and 6-month landmark analysis (HR: 0.51). The OS advantage was observed in both patients with NSCLC (HR: 0.36) and SCLC (HR: 0.27). Additional research is needed to validate the role of e-irAEs as an independent predictor of survival outcomes in patients with LC.

High-throughput transcriptome profiling indicates ribosomal RNAs to be associated with resistance to immunotherapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Despite the impressive outcomes with immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC), only a minority of the patients show long-term benefits from ICI. In this study, we used retrospective cohorts of ICI treated patients with NSCLC to discover and validate spatially resolved protein markers associated with resistance to programmed cell death protein-1 (PD-1) axis inhibition. METHODS: Pretreatment samples from 56 patients with NSCLC treated with ICI were collected and analyzed in a tissue microarray (TMA) format in including four different tumor regions per patient using the GeoMx platform for spatially informed transcriptomics. 34 patients had assessable tissue with tumor compartment in all 4 TMA spots, 22 with leukocyte compartment and 12 with CD68 compartment. The patients' tissue that was not assessable in fourfold redundancy in each compartment was designated as the validation cohort; cytokeratin (CK) (N=22), leukocytes CD45 (N=31), macrophages, CD68 (N=43). The human whole transcriptome, represented by~18,000 individual genes assessed by oligonucleotide-tagged in situ hybridization, was sequenced on the NovaSeq platform to quantify the RNAs present in each region of interest. RESULTS: 54,000 gene variables were generated per case, from them 25,740 were analyzed after removing targets with expression lower than a prespecified frequency. Cox proportional-hazards model analysis was performed for overall and progression-free survival (OS, PFS, respectively). After identifying genes significantly associated with limited survival benefit (HR>1)/progression per spot per patient, we used the intersection of them across the four TMA spots per patient. This resulted in a list of 12 genes in the tumor-cell compartment (RPL13A, GNL3, FAM83A, CYBA, ACSL4, SLC25A6, EPAS1, RPL5, APOL1, HSPD1, RPS4Y1, ADI1). RPL13A, GNL3 in tumor-cell compartment were also significantly associated with OS and PFS, respectively, in the validation cohort (CK: HR, 2.48; p=0.02 and HR, 5.33; p=0.04). In CD45 compartment, secreted frizzled-related protein 2, was associated with OS in the discovery cohort but not in the validation cohort. Similarly, in the CD68 compartment ARHGAP and PNN interacting serine and arginine rich protein were significantly associated with PFS and OS, respectively, in the majority but not all four spots per patient. CONCLUSION: This work highlights RPL13A and GNL3 as potential indicative biomarkers of resistance to PD-1 axis blockade that might help to improve precision immunotherapy strategies for lung cancer.

Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond.

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC.

Takotsubo Cardiomyopathy in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Summary of Included Cases.

BACKGROUND: There are emerging reports of Takotsubo syndrome (TTS) in cancer patients treated with immune checkpoint inhibitors (ICIs); however, the association of the two remains uncertain. METHODS: A systematic literature review was performed in the PubMed database and web sources (Google Scholar) according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. Case reports/series or studies including cancer patients treated with ICIs and presenting with TTS were considered. RESULTS: Seventeen cases were included in the systematic review. Most patients were males (59%) with median age of 70 years (30-83). Most common tumor types were lung cancer (35%) and melanoma (29%). Most patients were on first-line immunotherapy (35%) and after the first cycle (54%) of treatment. The median time on immunotherapy at the time of TTS presentation was 77 days (1-450). The most used agents were pembrolizumab and the combination of nivolumab-ipilimumab (35%, respectively). Potential stressors were recognized in 12 cases (80%). Six patients (35%) presented with concurrent cardiac complications. Corticosteroids were used in the management of eight patients (50%). Fifteen patients (88%) recovered from TTS, two patients (12%) relapsed, and one patient died. Immunotherapy was reintroduced in five cases (50%). CONCLUSION: TTS may be associated with immunotherapy for cancer. Physicians should be alert for TTS diagnosis in any patient with myocardial infarction-like presentation under treatment with ICIs.

Eligibility for screening with low-dose CT in a real-world cohort of patients with lung cancer in Greece: A brief report.

INTRODUCTION: NELSON and NLST prompted the implementation of lung cancer screening programs in the United States followed by several European countries. This study aimed to assess the sensitivity of different screening criteria among patients with lung cancer in Greece and investigate reasons for ineligibility. METHODS: We performed a retrospective analysis on patients with lung cancer referred to the largest referral center in Athens, Greece, between June 2014 and May 2023. The proportion of patients who would meet the updated USPSTF and NLST criteria was compared to the corresponding proportion of the Greek population over 15 years of age. RESULTS: Out of 2434 patients with lung cancer, 77.4 % (N = 1883) would meet the updated USPSTF criteria, and 58.9 % (N = 1439) would meet the NLST criteria at diagnosis; the corresponding proportions for the Greek population over 15 years would be 13.8 % and 8.2 %, respectively. Ineligible patients were more likely to be female, former or never-smokers, have adenocarcinoma histology, and have driver mutations (p < 0.001). CONCLUSIONS: Although the updated USPSTF criteria demonstrated good sensitivity, a substantial proportion of patients with lung cancer would still not be eligible for screening. Future studies to shape a comprehensive screening strategy should focus on the incorporation of additional risk factors for lung cancer, including air pollution and individual genetic susceptibility.

Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with newly diagnosed, stage IVA-IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes. RESULTS: Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration. CONCLUSIONS: Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration. TRIAL REGISTRATION NUMBER: NCT03162731.

Quantitative, Spatially Defined Expression of Leukocyte-associated Immunoglobulin-like Receptor in Non-small Cell Lung Cancer.

Targeting the interaction of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) and its ligands has been shown to reinstate antitumor immunity. In addition, the introduction of the LAIR-1 decoy protein, LAIR-2, sensitizes previously resistant lung tumors to programmed death-1 (PD-1) blockade, indicating the potential of LAIR-1 as an alternative marker for anti-PD-1 resistance in lung cancer. Here, we assessed LAIR-1 as compared with programmed death-ligand 1 (PD-L1) expression in various tumors, with a focus on non-small cell lung cancer (NSCLC) and its histologic subtypes using multiplexed quantitative immunofluorescence (mQIF) in 287 (discovery cohort) and 144 (validation cohort) patients with NSCLC. In addition, using multispectral imaging technology on mQIF images, we evaluated the localization of LAIR-1 on various cell types. We observed that CD14+, CD68+, and CD163+ monocytes and CK+ tumor cells predominantly expressed LAIR-1 more than other cell types. Furthermore, LAIR-1 expression in the tumor compartment was significantly higher in patients with lung adenocarcinoma (LUAD) than those with lung squamous cell carcinoma subtype (**, P = 0.003). Our results indicated that high tumor LAIR-1 expression in patients with LUAD is negatively associated with OS (overall survival, HR = 2.4; *, P = 0.02) highlighting its prognostic value in LUAD but not in other subtypes. The Pearson correlation between LAIR-1 and PD-L1 is 0.31; however, mutual exclusive staining pattern (i.e., several cases were positive for LAIR-1 and negative for PD-L1) was observed. Altogether, our data suggest that the combination therapy of anti-PD-1/PD-L1 with anti-LAIR-1 or the anti-LAIR-1 monotherapy alone may be promising cancer immunotherapeutic strategies. Significance: The spatial, quantitative assessment of LAIR-1 in NSCLC shows positive association of OS with high LAIR-1+/CD68+ cell densities and negative association of OS with high LAIR-1 expression in LUAD tumor subtype.

Programmed cell death protein 1 axis blockade in locally advanced squamous cell carcinoma of the head and neck: Neoadjuvant and adjuvant approaches.

Immunotherapy and in particular programmed cell death protein 1 (PD-1) inhibitors have been applied not only in the management of recurrent or metastatic disease but also as component of potentially curative treatment for many solid tumors. The incorporation of immunotherapy as neoadjuvant and /or adjuvant therapy in the treatment paradigm of locally advanced squamous cell carcinoma of the head and neck (SCCHN) is appealing with the goals of enhancing antitumor efficacy and, at the same time, reduce toxicity. This review analyzes the rationale for employing immunotherapy in the neoadjuvant and adjuvant settings, reviews the results of relevant clinical trials, and examines the potential benefits and caveats of neoadjuvant and/or adjuvant approaches in patients with SCCHN.

CD24: A Novel Target for Cancer Immunotherapy.

Cluster of differentiation 24 (CD24) is a small, highly glycosylated cell adhesion protein that is normally expressed by immune as well as epithelial, neural, and muscle cells. Tumor CD24 expression has been linked with alterations in several oncogenic signaling pathways. In addition, the CD24/Siglec-10 interaction has been implicated in tumor immune evasion, inhibiting macrophage-mediated phagocytosis as well as natural killer (NK) cell cytotoxicity. CD24 blockade has shown promising results in preclinical studies. Although there are limited data on efficacy, monoclonal antibodies against CD24 have demonstrated clinical safety and tolerability in two clinical trials. Other treatment modalities evaluated in the preclinical setting include antibody-drug conjugates and chimeric antigen receptor (CAR) T cell therapy. In this review, we summarize current evidence and future perspectives on CD24 as a potential target for cancer immunotherapy.

Immune Checkpoint Blockade in Hormone Receptor-Positive Breast Cancer: Resistance Mechanisms and Future Perspectives.

Anti-programmed cell death protein 1 immunotherapy has been incorporated in the treatment algorithm of triple-negative breast cancer (TNBC). However, clinical trial results for patients with hormone receptor (HR)-positive disease appear less compelling. HR-positive tumors exhibit lower levels of programmed death-ligand 1 expression in comparison with their triple-negative counterparts. Moreover, signaling through estrogen receptor alters the immune microenvironment, rendering such tumors immunologically "cold." To explain differential responses to immune checkpoint blockade, this review interrogates differences between HR-positive and TNBC. Starting from distinct genomic features, we further present disparities concerning the tumor microenvironment and finally, we summarize early-phase clinical trial results on promising novel immunotherapy combinations.

New Insights into SARS-CoV-2 and Cancer Cross-Talk: Does a Novel Oncogenesis Driver Emerge?

Since the pandemic's onset, a growing population of individuals has recovered from SARS-CoV-2 infection and its long-term effects in some of the convalescents are gradually being reported. Although the precise etiopathogenesis of post-acute COVID-19 sequelae (PACS) remains elusive, the mainly accepted rationale is that SARS-CoV-2 exerts long-lasting immunomodulatory effects, promotes chronic low-grade inflammation, and causes irreversible tissue damage. So far, several viruses have been causally linked to human oncogenesis, whereas chronic inflammation and immune escape are thought to be the leading oncogenic mechanisms. Excessive cytokine release, impaired T-cell responses, aberrant activation of regulatory signaling pathways (e.g., JAK-STAT, MAPK, NF-kB), and tissue damage, hallmarks of COVID-19 disease course, are also present in the tumor microenvironment. Therefore, the intersection of COVID-19 and cancer is partially recognized and the long-term effects of the virus on oncogenesis and cancer progression have not been explored yet. Herein, we present an up-to-date review of the current literature regarding COVID-19 and cancer cross-talk, as well as the oncogenic pathways stimulated by SARS-CoV-2.

Vaccine-Related Autoimmune Hepatitis: Emerging Association with SARS-CoV-2 Vaccination or Coincidence?

BACKGROUND: There is an increasing number of liver injury cases resembling autoimmune hepatitis (AIH) following SARS-CoV-2 vaccination; however, an association has not yet been established. METHODS/MATERIALS: A literature review was performed to identify articles regarding the association of AIH with vaccination, emphasizing on SARS-CoV-2 vaccines, and the proposed mechanisms. We then performed a literature search for AIH-like cases following SARS-CoV-2 vaccination, and we evaluated the included cases for AIH diagnosis using simplified diagnostic criteria (SDC), and for vaccination causality using the Naranjo score for adverse drug reactions. RESULTS: We identified 51 AIH-like cases following SARS-CoV-2 vaccination. Forty cases (80%) were characterized as "probable", "at least probable", or "definite" for AIH diagnosis according to SDC. Forty cases (78.4%) were characterized as "probable", four (7.8%) as "possible", and three (5.8%) as "definite" for vaccine-related AIH according to the Naranjo score. CONCLUSION: SARS-CoV-2 vaccine-related AIH carries several phenotypes and, although most cases resolve, immunosuppressive therapy seems to be necessary. Early diagnosis is mandatory and should be considered in any patient with acute or chronic hepatitis after SARS-CoV-2 vaccination, especially in those with pre-existing liver disease.

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities.

A vital function of the immune system is the modulation of an evolving immune response. It is responsible for guarding against a wide variety of pathogens as well as the establishment of memory responses to some future hostile encounters. Simultaneously, it maintains self-tolerance and minimizes collateral tissue damage at sites of inflammation. In recent years, the regulation of T-cell responses to foreign or self-protein antigens and maintenance of balance between T-cell subsets have been linked to a distinct class of cell surface and extracellular components, the immune checkpoint molecules. The fact that both cancer and viral infections exploit similar, if not the same, immune checkpoint molecules to escape the host immune response highlights the need to study the impact of immune checkpoint blockade on viral infections. More importantly, the process through which immune checkpoint blockade completely changed the way we approach cancer could be the key to decipher the potential role of immunotherapy in the therapeutic algorithm of viral infections. This review focuses on the effect of programmed cell death protein 1/programmed death-ligand 1 blockade on the outcome of viral infections in cancer patients as well as the potential benefit from the incorporation of immune checkpoint inhibitors (ICIs) in treatment of viral infections.

Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade.

Treatment with immune checkpoint inhibitors has altered the course of malignant melanoma, with approximately half of the patients with advanced disease surviving for more than 5 years after diagnosis. Currently, there are no biomarker methods for predicting outcome from immunotherapy. Here, we obtained transcriptomic information from a total of 105 baseline tumor samples comprising two cohorts of patients with advanced melanoma treated with programmed cell death protein 1 (PD-1)-based immunotherapies. Gene expression profiles were correlated with progression-free survival (PFS) within consecutive clinical benefit intervals (i.e., 6, 12, 18, and 24 months). Elastic net binomial regression models with cross validation were utilized to compare the predictive value of distinct genes across time. Lasso regression was used to generate a signature predicting long-term benefit (LTB), defined as patients who remain alive and free of disease progression at 24 months post treatment initiation. We show that baseline gene expression profiles were consistently able to predict long-term immunotherapy outcomes with high accuracy. The predictive value of different genes fluctuated across consecutive clinical benefit intervals, with a distinct set of genes defining benefit at 24 months compared to earlier outcomes. A 12-gene signature was able to predict LTB following anti-PD-1 therapy with an area under the curve (AUC) equal to 0.92 and 0.74 in the training and validation set, respectively. Evaluation of LTB, via a unique signature may complement objective response classification and characterize the logistics of sustained antitumor immune responses.