Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10-deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.

Highlights d scRNA-seq analyses highlight conserved myeloid subsets in human and murine CRC d Two distinct TAM subsets show inflammatory and angiogenic signatures, respectively d Two distinct TAM subsets show differential sensitivity to CSF1R blockade d Anti-CD40 activates specific cDC1s and expands Th1-like and CD8 + memory T cells

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Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.

There has been conflicting evidence concerning the possible association between tuberculosis (TB) and subsequent risk of lung cancer. To investigate whether currently published epidemiological studies can clarify this association, we performed a systematic review of 37 case-control and 4 cohort studies (published between January 1966 and January 2009) and a meta-analysis of risk estimates, with particular attention to the role of smoking, passive smoking and the timing of diagnosis of TB on this relationship. Data for the review show a significantly increased lung cancer risk associated with preexisting TB. Importantly, the association was not due to confounding by the effects of tobacco use (RR 5 1.8, 95% confidence interval (CI) 5 1.4-2.2, among never smoking individuals), lifetime environmental tobacco smoke exposure (RR 5 2.9, 95%CI 5 1.6-5.3, after controlling) or the timing of diagnosis of TB (the increased lung cancer risk remained 2-fold elevated for more than 20 years after TB diagnosis). Interestingly, the association was significant with adenocarcinoma (RR 5 1.6, 95%CI 5 1.2-2.1), but no significant associations with squamous and small cell type of lung cancer were observed. Although no causal mechanism has been demonstrated for such an association, present study supports a direct relation between TB and lung cancer, especially adenocarcinomas. ' UICCKey words: systematic review; tuberculosis; meta-analysis; lung cancer Lung cancer as the most common cancer in the world represents a major public health problem. Worldwide it accounts for approximately 1.2 million cancer-related deaths each year.1 In men it is the largest cause of mortality, and in women it is the third largest cause, just after breast and intestinal cancer, but before cervical cancer.2-4 Good prevention and early detection of breast and cervical cancer mean that lung cancer will be the leading cause of mortality in women worldwide, too.5 Tuberculosis (TB) is another major cause of morbidity and mortality, especially in developing countries. Worldwide, approximately one third of people are infected with Mycobacterium tuberculosis, the causative microorganism, and with aging or weakening of the immune system, this infection can reactivate, leading to severe and prolonged pneumonia, pulmonary scarring and wasting.6 It has been well documented that lung inflammation and fibrosis from TB could induce genetic damage, which may increase the risk of lung cancer. [7][8][9] Along these lines, a number of retrospective case-control/prospective cohort studies have reported that subjects with a history of preexisting TB experience excess risk of lung cancer. However, the evidence has been inconsistent, and there has also been uncertainty about the temporal relationship between previous TB and lung cancer and possible residual confounding by cigarette smoking, passive smoking and the timing of diagnosis of TB. The determination of whether or not there is such an association has potential importance for managing TB, for screening of lung cancer an...