Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1–5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.

We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis− group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome.

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The entire known turtle and crocodile faunas of Thailand and adjacent waters are treated, based on collections in Chulalongkorn University in Bangkok and in part on specimens in the EHT-HMS collection in Lawrence, Kansas. The number of species and subspecies here reported is 23 turtles and 3 crocodiles. Certain other specimens of turtles in the Bangkok Zoological Gardens purporting to be from Thailand have been examined. Some of these may also have a place in the Thai fauna, but their provenance is uncertain, some certainly not from Thailand.Map 1. Provinces (Changwats) of Thailand. The numbers refer to the adjoining list of provincial names, and have no significance in themselves. The University Science Bulletin TESTUDINES General Consideration of the Testudines A considerable number of the herpetologists of the 19th century contributed to the understanding and description of the species, genera, famihes, and higher groups of the turtles. Cope proposed a suborder Athecae for the huge sea turtle (Leathery Turtle) thus separating the one family, genus, and species (two subspecies) from all other turtles. This has been rather generally accepted by herpetologists. However, Mertens and Wermuth, 1955, in a critical list of the recent turtles, do not recognize the suborder Athecae but place its family Dermochelydidae with the family Cheloniidae under a Sectio Chelonioidea (superfamily?), a treatment which may be questioned. Boulenger's "Catalogue of the chelonians, rhynchocephalians, and crocodiles" published in 1889 served largely as a guide to turtle classification. In 1909 Siebenrock published his "Synopsis der rezenten Schildkroten mit Berucksichtigung der in historischer Zeit ausgestorben en Arten." This tended to replace as a guide the earlier listing of Boulenger. Williams (1952) offered a tentative arrangement of the Testudinata of the world. The more recent work is that of Mertens and Wermuth (1955), "Die rezenten Schildroten, Krokodile und Briickenechsen: eine kritische Liste der heute lebenden Arten und Rassen." J. E. Gray, who was largely responsible for the description of genera and species of Asiatic turtles, was able to recognize a number of genera which Boulenger disregarded or rejected. Certain of these were resurrected by Genus Dermochelys Blainville

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