The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration.

We wanted to analyze whether tumor HLA class I (HLA-I) expression influences the pattern of the immune cell infiltration and stromal cell reaction in the tumor microenvironment. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. 28 patients out of the 57 were completely negative for HLA-I expression (49.1%) or showed a selective HLA-A locus downregulation (three patients, 5.2%). In 26 out of 57 tumors (47.8%) we detected a positive HLA-I expression but with a percentage of HLA-I negative cells between 10 and 25%. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of ß2-microglobulin (ß2-m) and LMP2 and LMP7 antigen presentation machinery genes. The analysis and localization of different immune cell populations revealed the presence of two major and reproducible patterns. One pattern, which we designated "immune-permissive tumor microenvironment (TME)," was characterized by positive tumor HLA-I expression, intratumoral infiltration with cytotoxic T-CD8+ cells, M1-inflammatory type macrophages, and a diffuse pattern of FAP+ cancer-associated fibroblasts. In contrast, another pattern defined as "non-immune-permissive TME" was found in HLA-I negative tumors with strong stromal-matrix interaction, T-CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair-type macrophages. In conclusion, this study revealed marked differences between HLA class I-positive and negative tumors related to tissue structure, the composition of leukocyte infiltration and stromal response in the tumor microenvironment.

The Polemic Diagnostic Role of TP53 Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers.

Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.

Cooperative and Escaping Mechanisms between Circulating Tumor Cells and Blood Constituents.

Metastasis is the leading cause of cancer-related deaths and despite measurable progress in the field, underlying mechanisms are still not fully understood. Circulating tumor cells (CTCs) disseminate within the bloodstream, where most of them die due to the attack of the immune system. On the other hand, recent evidence shows active interactions between CTCs and platelets, myeloid cells, macrophages, neutrophils, and other hematopoietic cells that secrete immunosuppressive cytokines, which aid CTCs to evade the immune system and enable metastasis. Platelets, for instance, regulate inflammation, recruit neutrophils, and cause fibrin clots, which may protect CTCs from the attack of Natural Killer cells or macrophages and facilitate extravasation. Recently, a correlation between the commensal microbiota and the inflammatory/immune tone of the organism has been stablished. Thus, the microbiota may affect the development of cancer-promoting conditions. Furthermore, CTCs may suffer phenotypic changes, as those caused by the epithelial-mesenchymal transition, that also contribute to the immune escape and resistance to immunotherapy. In this review, we discuss the findings regarding the collaborative biological events among CTCs, immune cells, and microbiome associated to immune escape and metastatic progression.

Perioperative outcome of lung cancer surgery in women: results from a Spanish nationwide prospective cohort study.

BACKGROUND: To assess possible differences in the perioperative profile between men and women in lung cancer surgery. METHODS: A prospective cohort multicenter study was design, in which consecutive patients undergoing curative intent surgery for lung cancer in 24 Thoracic Services throughout Spain were included. Clinical features, tumor- and surgery-related data, postoperative complications, and mortality were recorded. RESULTS: There were 2,566 men and 741 women. Women were younger than men [mean (SD) age, 61.8 (10.8) vs. 66.5 (9.1) years, P<0.0001] and showed a more favorable preoperative characteristics, with significantly higher percentages of ECOG grade 0 and lower percentages of active smokers (28.4% vs. 33.9%; pack-years 18.8 vs. 26.9) and comorbidities [chronic obstructive pulmonary disease (COPD), diabetes, hypertension, cardiac disorders]. There were significant differences (P<0.001) in histological types and TNM stages with adenocarcinoma (70.1% vs. 46.4%) and IA stage (41.5% vs. 33.6%) more frequent in women. The use of VATS or thoracotomy was similar. The rate of pneumonectomy was higher in men (10.9%) than in women (5.1%) (P<0.001) but the distributions of other procedures were similar. Postoperative complications (pneumonitis, atelectasis, air leak, hemorrhage, fistula, empyema, wound dehiscence, and need of reintubation) were lower in women. Significant differences (P<0.0001) in the severity of postoperative complications (Clavien-Dindo classification) were also found, with higher percentages of grades I (51.6% vs. 43%) and II (37.5% vs. 33%) and lower percentages of grades III and IV among women. The mean length of hospital stay was 7.8 (7.1) days in men versus 6.3 (5.0) days in women, and the 30-day mortality rate 0.3% in women versus 2.9% in men (P<0.0001). The percentage of readmissions within 30 days after surgery was also higher in men (8.6% vs. 2.8%). CONCLUSIONS: This multicenter nationwide study of lung cancer surgery with curative intent shows that the perioperative profile is better in women than in men.

Initial single-port thoracoscopy to reduce surgical trauma during open en bloc chest wall and pulmonary resection for locally invasive cancer.

OBJECTIVES: En bloc pulmonary and chest wall resection is the preferred method of treatment for locally invasive lung carcinoma. However, it carries major trauma to the chest wall, especially in cases with chest wall involvement distant to the potential location of 'traditional' thoracotomies. We describe an alternative method of estimating the boundaries of chest wall resection employing video assisted thoracoscopic surgery (VATS) and hypodermic needles. METHODS: VATS delineation of boundaries of chest wall involvement by lung cancer has been performed in six patients who gave written consent. In one case the single-port thoracoscopic examination revealed unexpected distant pleural metastases thus preventing from resection. The other 5 patients, three males and two females [median age of 60.5 (range 39 to 75) years] underwent en bloc anatomical lung resection in addition to chest wall excision and reconstruction for T3N0 lung cancer. RESULTS: In these five cases the chest wall opening was restricted to the extent of the rib excision, and the pulmonary resection was performed via the existing chest wall opening without requiring extension of the thoracotomy or any rib spreading. DISCUSSION: Minimally invasive techniques aid to delineate the boundaries of chest wall involvement of lung cancer and intraoperative staging. This helped tailoring the surgical approach and location of the thoracotomy, and prevented rib-spreading or additional thoracotomies in our cases.