Tumor-associated tertiary lymphoid structures in cancer: implications for immunotherapy.

INTRODUCTION: Tertiary lymphoid structures (TLS) arise at chronic inflammatory sites where they function as miniature lymph nodes to generate immune responses, which can be beneficial or detrimental, in diseases as diverse as autoimmunity, chronic infections and cancer. A growing number of studies show that a TLS presence in tumors from cancer patients treated with immune checkpoint inhibitors is closely linked with improved clinical outcomes. TLS may foster the generation of specific anti-tumor immune responses and immunological memory that recognizes a patient's own tumor. Due to repeated rounds of chronic inflammation, some tumor-associated TLS may be immunologically inactive, with immune checkpoint inhibitors functioning to revitalize them through pathway activation.This review summarizes work on TLS and how they mediate immune responses in human tumors. We also explore TLS as potential prognostic and predictive biomarkers for immunotherapy. EXPERT OPINION: The presence of TLS in human tumors has been linked with a better clinical prognosis, response to treatment(s) and overall survival. TLS provide a structured microenvironment for the activation, expansion and maturation of immune cells at the tumor site. These activities can enhance the efficacy of immunotherapeutic treatments such as checkpoint inhibitors and cancer vaccines by revitalizing local anti-tumor immunity.

Can we yet use tertiary lymphoid structures as predictive biomarkers for immunotherapy response in melanoma?

PURPOSE OF REVIEW: In this review, we explore the potential of tertiary lymphoid structures (TLS) as predictive biomarkers in the response to immunotherapy for melanoma patients. RECENT FINDINGS: The significance of TLS as indicators predicting immunotherapy response becomes particularly pronounced. Melanoma, renowned for its aggressive characteristics, has undergone revolutionary transformations in treatment through immunotherapeutic interventions. Investigations have unveiled a compelling correlation between the presence of TLS in the melanoma tumor microenvironment and favorable responses to immunotherapy. These responses, characterized by heightened survival rates and improved clinical outcomes, imply that TLS might be pivotal in tailoring more efficient and personalized treatments for individuals with melanoma. The ongoing discourse regarding TLS as a predictive biomarker underscores the need for a meticulous examination of its potential in guiding clinical decisions and optimizing therapeutic strategies. SUMMARY: TLS show great promises as potential biomarkers to melanoma patient's outcomes in ICI treatment; however, more studies are needed to understand their mechanisms of actions and the long-term impact of their functionality.

Single agent vs combination immunotherapy in advanced melanoma: a review of the evidence.

PURPOSE OF REVIEW: The aim of this review is to outline the current landscape of advanced melanoma treatment options, provide insights on selecting combination therapies within different clinical scenarios, capture clinical relevance of anti-programmed cell death protein 1 (PD-1) monotherapy, and explore the unmet needs with immune check-point inhibitors (ICI) in advanced melanoma. RECENT FINDINGS: ICI based treatment consisted of single agent ICI or dual combination ICI-ICI is the standard of care of front-line treatment of metastatic or unresectable melanoma. PD-1 inhibitors (Pembrolizumab and Nivolumab) improved progression free survival (PFS) and overall survival (OS) compared to chemotherapy and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors (Ipilimumab and Tremelimumab). The dual ICI combination (Nivolumab and Ipilimumab) provided profound and durable responses better than monotherapy, and the longest overall survival ever achieved in advanced disease, including in patients with murine sarcoma viral oncogene homolog B (BRAF)-mutated disease, but at the cost of a high risk of severe toxicity. The new dual blockage of LAG-3 and PD-1 (Nivolumab-Relatlimab) emerges as a valid option with promising efficacy outcomes and a favourable toxicity profile. Mature survival data is still needed to capture the real benefit. SUMMARY: These new plethora of options pose new challenges not only for optimal treatment sequencing strategies but especially for management of adverse effects, endorsing the need to integrate a holistic and personalized approach for patient care.

Thromboembolism and Immune Checkpoint Blockade in Cancer Patients: An Old Foe for New Research.

Patients with cancer are at an increased risk of venous (VTE) and arterial thromboembolism (ATE), and thromboembolic events (TEs) represent the second-leading cause of death in cancer patients. The risk of cancer-associated thromboembolism is multifactorial. In addition to patient risk factors, anticancer treatments have been found to increase the risk of both VTE and ATE. Immune checkpoint blockade (ICB) has become a mainstay of treatment in various types of cancers. Their use is associated with the occurrence of a new spectrum of side effects called immune-related adverse events. Meta-analyses-including data from prospective and retrospective studies-and case reports both reported VTE and ATE as adverse events associated with ICB, with a cumulative incidence equaling around 3% and 1%, respectively. The exact mechanism underlying a TE after ICB use is currently unclear, as well as its associated risk factors. Considering their potential life-threatening impact, it is important for clinicians to be aware of the potential thrombotic complications, to educate patients and recognize early signs and symptoms of VTE and ATE, in order to allow prompt treatment (if needed) and avoid complications.

Biomarkers and immunotherapy: where are we?

PURPOSE OF REVIEW: Here, we reviewed the recent breakthroughs in the understanding of predictive biomarkers for immune checkpoint inhibitors (ICI) treatment. RECENT FINDINGS: ICI have revolutionized cancer therapy enabling novel therapeutic indications in multiple tumor types and increasing the probability of survival in patients with metastatic disease. However, in every considered tumor types only a minority of patients exhibits clear and lasting benefice from ICI treatment, and due to their unique mechanism of action treatment with ICI is also associated with acute clinical toxicities called immune related adverse events (irAEs) that can be life threatening. The approval of the first ICI drug has prompted many exploratory strategies for a variety of biomarkers and have shown that several factors might affect the response to ICI treatment, including tumors intrinsic factors, tumor microenvironment and tumor extrinsic or systemic factor. Currently, only three biomarkers programmed death-ligand 1 (PD-L1), tumor microenvironment and microsatellite instability had the US Food and Drug Administration-approbation with some limitations. SUMMARY: The establishment of valid predictive biomarkers of ICI sensitivity has become a priority to guide patient treatment to maximize the chance of benefit and prevent unnecessary toxicity.

A Rare Case of Hepatic Vanishing Bile Duct Syndrome Occurring after Combination Therapy with Nivolumab and Cabozantinib in a Patient with Renal Carcinoma.

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.

The impact of tumor cell metabolism on T cell-mediated immune responses and immuno-metabolic biomarkers in cancer.

The role of adaptive immunity is increasingly recognized as an important element both in the process of tumorigenesis and in the patient's response to treatment. While this understanding has led to new therapeutic strategies that potentiate the activities of tumor infiltrating lymphocytes, only a minority of patients attain durable responses. Metabolic activities in the tumor microenvironment, including hypoxia and acidity, can adversely affect immune responses, making the identification of metabolic biomarkers critically important for understanding and employing immunotherapies.

Sequential use of protein kinase inhibitors potentiates their toxicity to melanoma cells: a rationale to combine targeted drugs based on protein expression inhibition profiles.

Targeted therapy has shown high efficacy in the treatment of metastatic melanoma with impressive response rates. However, resistance appears after a few months, underlining the need for simultaneous multiple signalling pathway inhibition to provide a durable benefit. The aim of our study was to evaluate the possible synergistic effect of various protein kinase inhibitor combinations targeting SRC, MEK, PI3K or JAK on the survival of representative melanoma cell lines with WTNRAS/WTBRAF and harbouring the most frequent mutations (Q61LNRAS/WTBRAF or WTNRAS/V600EBRAF). By comparing IC50s and protein inhibition profiles, cell exposure to a single inhibitor for 3 days (condition 1) showed that both WTBRAF lines were at least 15-fold more sensitive to SRC inhibition while V600EBRAF cells were 30-fold more sensitive to MEK inhibition, confirming that the latter cells are largely dependent on the MAPK pathway for growth. Concomitant treatment for 3 days (condition 2) revealed an antagonistic effect between SRC and JAK inhibitors as compared to treatment by each inhibitor alone in all 3 lines, supporting that both SRC and JAK stimulate the STAT pathway. Finally, sequential cell exposure to inhibitors by pre-treatment with a single effector at non-toxic but effective on target inhibition concentrations for 7 days followed by the addition of each of the other inhibitors for 3 days (condition 3) showed that MEK, PI3K or JAK inhibitor acted in synergy with the SRC inhibitor in both wild-type and Q61LNRAS cells, suggesting that the first inhibitor could activate the SRC/STAT compensatory signalling pathway. In conclusion, a treatment strategy consisting in a sequential use of targeted inhibitors to first render melanoma cells more dependent on alternative compensatory pathways that should subsequently be inhibited, may enhance efficacy. By contrast, concomitant exposure to various combinations of inhibitors at different concentrations failed to produce such effect, further supporting the importance of both the duration of cell exposure to inhibitors and their sequential use.