Immune system and melanoma biology: a balance between immunosurveillance and immune escape Immune system and melanoma biology: a balance between immunosurveillance and immune escape

Despite the relevant antitumor efficacy of immunotherapy in advanced non-small cell lung cancer (NSCLC), the results in patients whose cancer harbors activating epidermal growth factor receptor (EGFR) mutations are disappointing. The biological mechanisms underlying immune escape and both unresponsiveness and resistance to immunotherapy in EGFR-mutant NSCLC patients have been partially investigated. To this regard, lung cancer immune escape largely involves high amounts of adenosine within the tumor milieu with broad immunosuppressive effects. Indeed, besides immune checkpoint receptors and their ligands, other mechanisms inducing immunosuppression and including adenosine produced by ecto-nucleotidases CD39 and CD73 contribute to lung tumorigenesis and progression. Here, we review the clinical results of immune checkpoint inhibitors in EGFR-mutant NSCLC, focusing on the dynamic immune composition of EGFR-mutant tumor microenvironment. The adenosine pathway-mediated dysregulation of energy metabolism in tumor microenvironment is suggested as a potential mechanism involved in the immune escape process. Finally, we report the strong rationale for planning strategies of combination therapy with immune checkpoints blockade and adenosine signaling inhibition to overcome immune escape and immunotherapy resistance in EGFR-mutated NSCLC.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

Cutaneous basal cell carcinoma (BCC) is the most common type of human tumor, and its incidence rate is increasing worldwide. Up until a few years ago, therapeutic options have been limited for patients with advanced BCC (including metastatic and locally-advanced BCC). Over the last few years, promising systemic therapies have been investigated for the treatment of advanced BCC. In particular, the Hedgehog signaling inhibition has shown remarkable results for this population. Hedgehog inhibitors, represented by vismodegib and sonidegib, have been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of both locally advanced and metastatic BCC, with, generally, a good safety profile. Notwithstanding the late onset of BCC in the global population, associated with life expectancy increase, only a few clinical trials have evaluated the efficacy and safety profile of Hedgehog inhibitors in this complex and neglected population. Herein, we review the major mechanisms implicated in the pathogenesis of BCC focusing on the Hedgehog signaling pathway and its therapeutic role in the elderly population. Finally, we report two case reports of BCC elderly patients in order to demonstrate both efficacy and safety of the Hedgehog inhibitors.

Kaposi’s sarcoma (KS) is a rare inflammation- based vascular cancer involving the skin. The viral aetiology of KS is the Human Herpesvirus 8. KS may be frequently diagnosed in immunosuppressed kidneytransplanted patients, while is less common in patients with dialysis. It is known that various immunological abnormalities can lead to impaired immune status in uremic patients. It is noteworthy that despite the incidence of KS in patients with renal impairment, only few cases have reported efficacy and safety profile of KS targeting anti-cancer drugs in this kidney disease population. Herein, we report the first case of a symptomatic KS patient with renal disease in haemodialysis and focus on its therapeutic management. We also review the main data available from literature regarding the safety of KS therapy in dialysis patients.