Simultaneous targeting of TGF-ß/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor ß (TGF-ß). We report that a bifunctional fusion protein that simultaneously inhibits TGF-ß and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-ß trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.

High-throughput screening identified inherited genetic variations in the EGFR pathway contributing to skin toxicity of EGFR inhibitors.

AIM: To identify genomic variants in the EGFR pathway and in cytokines predisposing to skin toxicity from EGFR inhibitors. PATIENTS & METHODS: In 126 patients with cancer and EGFR inhibitor therapy skin toxicity was quantified and EGFR and inflammatory pathway genes were analyzed by deep sequencing. RESULTS: We found 1437 SNPs in the 382-kb target region. Three SNPs in EGFR intron 1 were found exclusively in patients without skin rash. Another EGFR intron 23 SNP was associated with skin rash, overall survival and IL8 plasma concentrations. Moreover, carriers of the PIK3R1 326I variant were predisposed to skin rash and better survival. CONCLUSION: Comprehensive pathway-based resequencing revealed some new but only moderately strong genomic predictors of skin toxicity.

Mitochondrial D-Loop polymorphism and microsatellite instability in prostate cancer and benign hyperplasia patients.

In this study mitochondrial D-Loop variations in Iranian prostate cancer and benign prostatic hyperplasia (BPH) patients were investigated. Tumour samples and corresponding non-cancerous prostate tissue from 40 prostate cancer patients and 40 age-matched BPH patients were collected. The entire mtD-loop region (16024-576) was amplified using the PCR method and products were gel-purified and subjected to direct nucleotide sequencing. A total of 129 variations were found, the most frequent being 263A-G and 310T-C among both BPH and prostate cancer patients. Variation of 309 C-T was significantly more frequent in prostate cancer patients (P value<0.05). Four novel variations were observed on comparison with the MITOMAP database. Novel variations were np16154delT, np366G-A, np389G-A and 56insT. There was no correspondence between the different variations and the age of subjects. Considering that D-loop variations were frequent in both BPH and prostate cancer patients in our study, the fact that both groups had high average age can be a possible contributing factor. D-loop polymorphisms and microsatellite instability can influence cell physiology and result in a benign or malignant phenotype. Significantly higher frequency of 309 C-T variation in cancer patients is a notable finding and must be a focus of attention in future studies.

TP53 gene expression in HPV-positive oral tongue SCC and its correlation with nodal metastasis.

In this study, we investigated the prevalence of human papilloma virus (HPV) infection and TP53 expression in patients with squamous cell carcinoma (SCC) of the tongue and, subsequently, its significance in cervical lymph node metastases and tumor differentiation. Sections of formalin-fixed, paraffin-embedded tissue blocks from 94 histologically confirmed tongue SCC cases were investigated in this study. Immunohistochemistry was used to study TP53 expression, and polymerase chain reaction (PCR) was performed for the detection of high risk HPV types (16 and 18). The frequency of HPV-16 and HPV-18 infection was 10.6% and 16%, respectively. Overexpression of TP53 was observed in 70.2% of patients. Young patients (aged below 45 years) comprised 20% of all patients. There was no significant association between TP53, HPV-16, or HPV 18 presence and higher stages of the tumor, tumor differentiation, or presence of nodal metastasis. Although an association between head and neck SCC and HPV infection is being recognized and reported, our data implicate that HPV infection or TP53 expression does not play a significant role in oral tongue SCC pathogenesis, differentiation, or metastasis, as seen in our patients.

Are GSTM1, GSTT1 and CAG repeat length of androgen receptor gene polymorphisms associated with risk of prostate cancer in Iranian patients?

We conducted this study to investigate whether CAG repeat length in androgen receptor gene and GSTM1 and GSTT1 polymorphisms influence prostate cancer risk in Iranian newly diagnosed cancer patients compared to age-matched BPH group and healthy individuals. DNA from 110 pathologically-confirmed prostate cancer patients, 99 age-matched men with Benign Prostatic Hyperplasia (BPH) and 100 healthy individuals were extracted and amplified by polymerase chain reaction (PCR). PCR products were examined by electrophoresis and sequencing. The mean number of CAG repeat in prostate cancer patients was significantly smaller than normal (19.9 vs 22.8; p < 0.0001) and BPH groups (19.9 vs 21.9; P < 0.0001) The mean difference between normal individuals and BPH group was also significant (21.9 vs. 22.8; P = 0.003). Presence of GSTM1 null genotype were significantly higher in cancer and BPH group vs. normal individuals (both P values < 0.0001). there was not seen association between GSTT1 null or positive genotype with cancer risk, but analysis of GSTM1 null and GSTT1 positive in combination was statistically associated with Prostate cancer risk (OR = 8.4, 95% CI 1.53-46.73). Our results showed that CAG repeat polymorphism in AR gene may act as a risk modifier and GSTM1 null genotypes also may be contributed to prostate cancer susceptibility in Iranian patients.