STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact.

The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.

MEM: An Algorithm for the Reliable Detection of Microsatellite Instability (MSI) on a Small NGS Panel in Colorectal Cancer.

PURPOSE: MEM is an NGS algorithm that uses Expectation-Maximisation to detect the presence of unstable alleles from the NGS sequences of five microsatellites (BAT-25, BAT-26, NR-21, NR-24 and NR-27). The purpose of this study was to compare the MEM algorithm with a reference PCR method (MSI-PCR) and MisMatch Repair protein immunohistochemistry (MMR-IHC). METHODS: FFPE colorectal cancer samples from 146 patients were analysed in parallel by MSI-PCR and NGS using the MEM algorithm. MMR-IHC results were available for 133 samples. Serial dilutions of an MSI positive control were performed to estimate the limit of detection. RESULTS: the MEM algorithm was able to detect unstable alleles of each microsatellite with up to a 5% allelic fraction. Of the 146 samples, 28 (19.2%) were MSI in MSI-PCR. MEM algorithm results were in perfect agreement with those of MSI-PCR, at both MSI status and individual microsatellite level (Cohen's kappa = 1). A high level of agreement was noted between MSI-PCR/MEM algorithm results and MMR-IHC results (Cohen's kappa = 0.931). CONCLUSION: the MEM algorithm can determine the MSI status of colorectal cancer samples on a small NGS panel, using only five microsatellites approved by international guidelines, and can be combined with screening for targetable mutations.

Clinical, Genetic and Innate Immunity Characteristics of Melanoma in Organ Transplant Recipients.

The aims of this study were to determine the clinical and histological characteristics of melanoma in transplant recipients, the mutation profile (BRAF, NRAS and c-KIT genes), and the immune tolerance of the tumour microenvironment by immunohistochemical study of the expression of indoleamine 2,3-dioxygenase (IDO), PD1, PD-L1, CD8 and FoxP3. The study population comprised patients who had undergone a renal transplant in Nantes University Hospital who developed post-transplantation melanoma. Twenty cases of melanoma out of 4,663 transplant recipients were studied. The results differed from the usual data with respect to melanoma site: 40% were located on the face and were of the malignant lentigo type. The mutation profile was concordant with that of the immunocompetent population. IDO was expressed in all the sections tested, while CD8, FoxP3, PD1 and PD-L1 were poorly expressed. This reflected a highly immunodepressed tumour environment, raising the question of the inductive role of IDO on tumour immune tolerance in patients presenting with long-term immunodepression.

Adoptive TIL transfer in the adjuvant setting for melanoma: long-term patient survival.

Two first analyses of our clinical trial on TIL as adjuvant therapy for melanoma were published in 2002 and 2007. We present here an update of the clinical results after a 17-year median followup. In this trial, disease-free patients were randomly assigned to receive either TIL/IL-2 or IL-2. The relapse-free survival (RFS) was the primary objective. Eighty-eight patients were enrolled. A new analysis performed in May 2013 did not show significant changes in RFS or OS duration. However, our first finding on the association between the number of invaded lymph nodes and TIL effectiveness was strengthened. The Cox model adjusted on this interaction showed for the first time a significant treatment effect when considering the overall population, both on the RFS and OS. Patients treated with TIL had a longer RFS (P = 0.023) or OS (P = 0.020). This study being with a very long followup (17 years), confirmed the association between TIL effectiveness and the number of invaded lymph nodes, indicating that a low tumor burden could be a crucial factor enhancing the curative effect of TIL in possible microscopic residual disease. Moreover, we confirmed that a prolonged survival was associated with the presence of specific TIL and a decrease in Foxp3 expression.