Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2γc mice, lacking lymphocytes and NK cells, and in Ifng mice, Ldha and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.

Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun-exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies.

Summary Background  The field cancerization concept in photodamaged patients suggests that the entire sun‐exposed surface of the skin has an increased risk for the development of (pre)‐malignant lesions, mainly epithelial tumours. Topical photodynamic therapy (PDT) is a noninvasive therapeutic method for multiple actinic keratosis (AK) with excellent outcome. Objectives  To evaluate the clinical, histological and immunohistochemical changes in human skin with field cancerization after multiple sessions of PDT with methylaminolaevulinate (MAL). Methods  Twenty‐six patients with photodamaged skin and multiple AK on the face received three consecutive sessions of MAL‐PDT with red light (37 J cm−2), 1 month apart. Biopsies before and 3 months after the last treatment session were taken from normal‐appearing skin on the field‐cancerized area. Immunohistochemical stainings were performed for TP‐53, procollagen‐I, metalloproteinase‐1 (MMP‐1) and tenascin‐C (Tn‐C). Results  All 26 patients completed the study. The global score for photodamage improved considerably in all patients (P < 0·001). The AK clearance rate was 89·5% at the end of the study. Two treatment sessions were as effective as three MAL‐PDT sessions. A significant decrease in atypia grade and extent of keratinocyte atypia was observed histologically (P < 0·001). Also, a significant increase in collagen deposition (P = 0·001) and improvement of solar elastosis (P = 0·002) were noticed after PDT. However, immunohistochemistry showed only a trend for decreased TP‐53 expression (not significant), increased procollagen‐I and MMP‐1 expressions (not significant) and an increased expression of Tn‐C (P = 0·024). Conclusions  Clinical and histological improvement in field cancerization after multiple sessions of MAL‐PDT is proven. The decrease in severity and extent of keratinocyte atypia associated with a decreased expression of TP‐53 suggest a reduced carcinogenic potential of the sun‐damaged area. The significant increase of new collagen deposition and the reduction of solar elastosis explain the clinical improvement of photodamaged skin.

These results show the efficacy of an LED system for ALA-PDT both in vitro and in vivo. ALA-PDT with the LED system showed a noninferiority regarding the clinical outcome in the treatment of AK compared with the incoherent lamp.

SummarySkin rejuvenating effects of photodynamic therapy (PDT) for photoaged skin has been well-documented in several clinical trials. Different photosensitizers (5-aminolevulinic acid, methyl aminolevulinate) and diverse light sources (light-emitting diodes, lasers, intense pulsed light) have been used with promising results. An improvement of lentigines, skin roughness, fine lines and sallow complexion has been achieved with PDT. These clinically evident effects are at least in part due to histologically proven increase of collagen and decrease of elastotic material in the dermis. Effective improvement of photoaged skin, simultaneous treatment and possibly also prevention of actinic keratoses, the possibility of repeated treatments and, in contrast to other procedures, limited and calculable side effects make PDT a promising procedure for skin rejuvenation. Sigrid